Benzoic acid, benzoic acid derivatives and heteroaryl carboxylic acid conjugates of hydrocodone, prodrugs, methods of making and use thereof

ABSTRACT

The presently described technology provides methods of treating a patient having moderate to severe pain, narcotic or opioid abuse or narcotic or opioid withdrawal. The presently described methods are carried out by comprising administering to the patient a pharmaceutically effective amount of a composition comprising acetaminophen and benzoate-hydrocodone hydrochloride. The composition has reduced side effects when compared with unconjugated hydrocodone.

RELATED APPLICATIONS

This application is a continuation-in-part of U.S. application Ser. No. 15/843,875, filed Dec. 15, 2017, which is a divisional of U.S. application Ser. No. 14/816,915, filed Aug. 3, 2015, which is a continuation-in-part of U.S. application Ser. No. 14/557,570, filed Dec. 2, 2014, which is a continuation of U.S. application Ser. No. 13/888,587, filed May 7, 2013, which is a continuation of U.S. application Ser. No. 12/828,381, filed Jul. 1, 2010, now U.S. Pat. No. 8,461,137, which claims priority to and benefit of U.S. provisional patent application No. 61/222,718, filed Jul. 2, 2009, all of which are herein incorporated by reference in their entireties.

FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

[Not Applicable]

BACKGROUND OF THE INVENTION

Opioids are highly effective as analgesics and are commonly prescribed for the treatment of acute and chronic pain. They are also commonly used as antitussives. The opioids, however, also produce euphoria and are highly addictive. As a result they are often abused with far reaching social and health related consequences.

Because of the inherent potential for abuse, it is desirable that any pharmaceutical composition containing an opioid agonist be made as abuse-resistant or abuse-deterrent as practical. Illicit users often will attempt to circumvent the extended release properties of these dosage forms by injecting or otherwise misusing the product in order to achieve an immediate release of the opioid agonist.

Despite their addictive properties and the potential for abuse, morphine-like drugs, particularly, codeine, hydrocodone, and oxycodone have been routinely prescribed as treatment for severe acute and chronic pain in recent decades. This is, in part, because there are no alternatives to relieve severe pain that is resistant to other less potent analgesics such as non-steroidal anti-inflammatory drugs (NSAIDS). In this regard, there is a need to decrease the abuse potential. Thus far, approaches taken, unfortunately, have not solved the problem.

Hydrocodone is an opioid analgesic and antitussive and occurs as fine, white crystals or as crystalline powder. Hydrocodone is a semisynthetic narcotic analgesic prepared from codeine with multiple actions qualitatively similar to those of codeine. It is mainly used for relief of moderate to moderately severe pain. Additionally, it is used as an antitussive in cough syrups and tablets in sub-analgesic doses (2.5-5 mg).

Patients taking opioid analgesics such as hydrocodone for pain relief can become unintentionally addicted. As tolerance to the opioids develops more drug is needed to alleviate the pain and generate the sense of wellbeing initially achieved with the prescribed dose. This leads to dose escalation, which if left unchecked can lead rapidly to addiction. In some cases, patients have become very addicted in as little as thirty days.

BRIEF SUMMARY OF THE INVENTION

The present technology, it is believed, utilizes conjugation through covalent bond formation between the opioid hydrocodone and certain aryl carboxylic acids to decrease its potential for causing overdose or abuse by requiring the active hydrocodone to be released through enzymatic or metabolic breakdown of the conjugate in vivo. The present technology also provides methods of delivering hydrocodone as conjugates that release the hydrocodone following oral administration while being resistant to abuse by circuitous routes such as intravenous (“shooting”) injection and intranasal administration (“snorting”).

The presently described technology in at least one aspect provides a slow/sustained/controlled release composition of conjugated hydrocodone that allows slow/sustained/controlled delivery of the hydrocodone and/or its active metabolite, hydromorphone, into the blood system of a human or animal within a safe therapeutic window upon, for example, oral administration. In certain embodiments of the presently described technology, compositions and formulations comprising the conjugated hydrocodone can lessen addiction/abuse potential and/or other common side effects associated with hydrocodone and similar compounds.

In one aspect, the present technology provides a composition comprising at least one conjugate of hydrocodone and at least one benzoic acid or derivative thereof, a salt thereof, or a combination thereof, the benzoic acid or derivative thereof having the following formula I:

where X, Y and Z are independently selected from the group consisting of H, O, S, NH and —(CH₂)_(x)—; R¹, R² and R³ are independently selected from the group consisting of H, alkyl, alkoxy, aryl, alkenyl, alkynyl, halo, haloalkyl, alkylaryl, arylalkyl, heterocycle, arylalkoxy, cycloalkyl, cycloalkenyl and cycloalkynyl; o, p, q are independently selected from 0 or 1; and x is an integer between 1 and 10. In some aspects, the benzoic acid or derivative thereof is an amino benzoate, a hydroxybenzoate, an aminohydroxybenzoate, a derivative thereof, or combination thereof.

In another aspect, the present technology provides a composition comprising at least one conjugate of hydrocodone and at least one benzoic acid, a derivative thereof, or a combination thereof.

In yet another aspect, the present technology provides conjugates of hydrocodone for use to treat pain, such as moderate to severe pain, acute pain, or chronic pain, or for use to reduce or prevent oral, intranasal or intravenous drug abuse. In some aspects, the conjugates provide oral, intranasal or parenteral drug abuse resistance.

In another aspect, the present technology provides at least one conjugate of hydrocodone that exhibits a slower rate of release over time and a greater or equal AUC when compared to an equivalent molar amount of unconjugated hydrocodone over the same time period. In other aspects, the conjugate of hydrocodone exhibits less variability in the oral PK profile when compared to unconjugated hydrocodone. In yet another aspect, at least one conjugate has reduced side effects when compared with unconjugated hydrocodone or prevents drug tampering by either physical or chemical manipulation.

In another aspect, at least one conjugate is provided in an amount sufficient to provide a therapeutically bioequivalent AUC when compared to an equivalent molar amount of unconjugated hydrocodone. In further aspects, at least one conjugate is provided in an amount sufficient to provide a therapeutically bioequivalent AUC when compared to an equivalent molar amount of unconjugated hydrocodone but does not provide a C_(max) spike or has a lower C_(max) than a therapeutically equivalent amount of unconjugated hydrocodone. In yet a further aspect, at least one conjugate is provided in an amount sufficient to provide a therapeutically bioequivalent AUC when compared to an equivalent molar amount of unconjugated hydrocodone, but does not provide an equivalent C_(max) spike. In some aspects, at least one conjugate provides an equivalent C_(max) spike when compared to unconjugated hydrocodone.

In yet another aspect, the present technology provides a method for treating a patient (human or animal) having a disease, disorder or condition requiring or mediated by binding of an opioid to the opioid receptors of the patient, comprising orally administering to the patient a pharmaceutically effective amount of at least one conjugate of hydrocodone and at least one benzoic acid or derivative thereof, a salt thereof, or a combination thereof, the benzoic acid or derivative thereof having formula I:

where X, Y and Z are independently selected from the group consisting of H, O, S, NH and —(CH₂)_(x)—; R¹, R² and R³ are independently selected from the group consisting of H, alkyl, alkoxy, aryl, alkenyl, alkynyl, halo, haloalkyl, alkylaryl, arylalkyl, heterocycle, arylalkoxy, cycloalkyl, cycloalkenyl and cycloalkynyl; o, p, q are independently selected from 0 or 1; and x is an integer between 1 and 10.

In a further aspect, the present technology provides a method for treating a patient having a disease, disorder or condition requiring or mediated by inhibiting binding of an opioid to the opioid receptors of the patient (human or animal), comprising orally administering to the patient a pharmaceutically effective amount of at least one conjugate of hydrocodone and at least one benzoic acid or derivative thereof, a salt thereof, or a combination thereof, the benzoic acid or derivative thereof having formula I:

wherein

X, Y and Z are independently selected from the group consisting of H, O, S, NH and —(CH₂)_(x)—; R¹, R² and R³ are independently selected from the group consisting of H, alkyl, alkoxy, aryl, alkenyl, alkynyl, halo, haloalkyl, alkylaryl, arylalkyl, heterocycle, arylalkoxy, cycloalkyl, cycloalkenyl and cycloalkynyl; o, p, q are independently selected from 0 or 1; and x is an integer between 1 and 10.

In some aspects, the present technology provides at least one conjugate that reversibly inhibits binding of an opioid to the opioid receptor of the patient (human or animal). In other aspects, at least one conjugate reversibly inhibits binding of an opioid to the opioid receptor of the patient (human or animal) without a CNS depressive effect.

In a further aspect, the present technology provides a method for treating a patient having a disease, disorder or condition (such as pain) which can be treated by binding of an opioid to the opioid receptors of the patient (human or animal), the method comprising orally administering to the patient a pharmaceutically effective amount of at least one conjugate of hydrocodone and at least one benzoic acid, a salt thereof, a derivative thereof or a combination thereof.

In another aspect, the present technology provides a method for treating a patient having a disease, disorder or condition (such as addiction) which can be treated by inhibiting binding of an opioid to the opioid receptors of the patient (human or animal), comprising orally administering to the patient a pharmaceutically effective amount of at least one conjugate of hydrocodone and at least one benzoic acid, a salt thereof, a derivative thereof or a combination thereof.

In yet another aspect, the present technology provides a pharmaceutical kit including a specified amount of individual doses in a package containing a pharmaceutically effective amount of at least one conjugate of hydrocodone and at least one benzoate, a salt thereof, a derivative thereof or a combination thereof, the benzoate having the formula I:

wherein X, Y and Z are independently selected from the group consisting of H, O, S, NH and —(CH₂)_(x)—; R¹, R² and R³ are independently selected from the group consisting of H, alkyl, alkoxy, aryl, alkenyl, alkynyl, halo, haloalkyl, alkylaryl, arylalkyl, heterocycle, arylalkoxy, cycloalkyl, cycloalkenyl and cycloalkynyl; o, p, q can be independently selected from 0 or 1; and x is an integer between 1 and 10. In some aspects, the kit further comprises instructions for use of the kit in a method for treating or preventing drug withdrawal symptoms or pain in a human or animal patient.

In another aspect, the present technology provides a pharmaceutical kit including a specified amount of individual doses in a package containing a pharmaceutically effective amount of at least one conjugate of hydrocodone and at least one benzoic acid, a salt thereof, a derivative thereof or a combination thereof. In some aspects, the kit further includes instructions for use of the kit in a method for treating or preventing drug withdrawal symptoms or pain in a human or animal patient.

In yet another aspect, the present technology provides a composition comprising at least one conjugate of hydrocodone and at least one heteroaryl carboxylic acid, a derivative thereof, or a combination thereof.

In yet another aspect, the present technology provides at least one conjugate of hydrocodone and at least one heteroaryl carboxylic acid, a derivative thereof, or a combination thereof where at least one heteroaryl carboxylic acid is selected from formula II, formula III or formula IV, wherein formula II, formula III and formula IV are:

wherein X, Y and Z are independently selected from the group consisting of H, O, S, NH and —(CH₂)_(x)—; R¹, R² and R³ are independently selected from the group consisting of H, alkyl, alkoxy, aryl, alkenyl, alkynyl, halo, haloalkyl, alkylaryl, arylalkyl, heterocycle, arylalkoxy, cycloalkyl, cycloalkenyl and cycloalkynyl; o, p, q are independently selected from 0 or 1; and x is an integer from 1 to 10. In some aspects, at least one heteroaryl carboxylic acid is a pyridine derivative.

In some aspects, the present technology provides at least one conjugate that prevents drug tampering by either physical or chemical manipulation.

In another aspect, the present technology provides a method for treating a patient having a disease, disorder or condition requiring or mediated by binding of an opioid to the opioid receptors of the patient (human or animal), comprising orally administering to the patient a pharmaceutically effective amount of at least one conjugate of hydrocodone and at least one heteroaryl carboxylic acid.

In a further aspect, the present technology provides a method for treating a patient having a disease, disorder or condition requiring or mediated by binding of an opioid to the opioid receptors of the patient (human or animal), comprising orally administering to the patient a pharmaceutically effective amount of at least one conjugate of hydrocodone and at least one heteroaryl carboxylic acid, where the heteroaryl carboxylic acid is selected from formula II, formula III or formula IV, wherein formula II, formula III and formula IV are:

where X, Y and Z are independently selected from the group consisting of H, O, S, NH and —(CH₂)_(x)—; R¹, R² and R³ are independently selected from the group consisting of H, alkyl, alkoxy, aryl, alkenyl, alkynyl, halo, haloalkyl, alkylaryl, arylalkyl, heterocycle, arylalkoxy, cycloalkyl, cycloalkenyl and cycloalkynyl; o, p, q are independently selected from 0 or 1; and x is an integer from 1 to 10.

In another aspect, the present technology provides a method for treating a patient having a disease, disorder or condition requiring or mediated by binding of an opioid to the opioid receptors of the patient, comprising orally administering to the patient a pharmaceutically effective amount of at least one conjugate of hydrocodone and at least one nicotinic acid, a derivative thereof, or a combination thereof.

In another aspect, the present technology provides a method for treating a patient having a disease, disorder or condition requiring or mediated by inhibiting binding of an opioid to the opioid receptors of the patient, comprising orally administering to the patient a pharmaceutically effective amount of at least one conjugate of hydrocodone and at least one heteroaryl carboxylic acid. In some aspects, the heteroaryl carboxylic acid is selected from formula II, formula III or formula IV, wherein formula II, formula III and formula IV are:

wherein X, Y and Z are independently selected from the group consisting of H, O, S, NH and —(CH₂)_(x)—; R¹, R² and R³ are independently selected from the group consisting of H, alkyl, alkoxy, aryl, alkenyl, alkynyl, halo, haloalkyl, alkylaryl, arylalkyl, heterocycle, arylalkoxy, cycloalkyl, cycloalkenyl and cycloalkynyl; o, p, q are independently selected from 0 or 1; and x is an integer from 1 to 10.

In another aspect, the present technology provides a method for treating a patient having a disease, disorder or condition requiring or mediated by inhibiting binding of an opioid to the opioid receptors of the patient, comprising orally administering to the patient a pharmaceutically effective amount of at least one conjugate of hydrocodone and at least one nicotinic acid, a derivative thereof, or a combination thereof.

In yet another aspect, the present technology provides a pharmaceutical kit including a specified number of individual doses in a package containing a pharmaceutically effective amount of at least one conjugate of hydrocodone and at least one heteroaryl carboxylic acid, a derivative thereof, or a combination thereof, wherein the heteroaryl carboxylic acid is selected from formula II, formula III or formula IV, wherein formula II, formula III and formula IV are:

wherein X, Y and Z are independently selected from the group consisting of H, O, S, NH and —(CH₂)_(x)—; R¹, R² and R³ are independently selected from the group consisting of H, alkyl, alkoxy, aryl, alkenyl, alkynyl, halo, haloalkyl, alkylaryl, arylalkyl, heterocycle, arylalkoxy, cycloalkyl, cycloalkenyl and cycloalkynyl; o, p, q are independently selected from 0 or 1; and x is an integer from 1 to 10. In some aspects, the kit further comprises instructions for use of the kit in a method for treating or preventing drug withdrawal symptoms or pain in a human or animal patient.

In yet another aspect, the present technology provides a prodrug comprising at least one conjugate of hydrocodone and at least one benzoic acid or benzoic acid derivative, a salt thereof, or a combination thereof, the benzoic acid or benzoic acid derivative having the following formula I:

where X, Y and Z are independently selected from the group consisting of H, O, S, NH and —(CH₂)_(x)—; R¹, R² and R³ are independently selected from the group consisting of H, alkyl, alkoxy, aryl, alkenyl, alkynyl, halo, haloalkyl, alkylaryl, arylalkyl, heterocycle, arylalkoxy, cycloalkyl, cycloalkenyl and cycloalkynyl; o, p, q are independently selected from 0 or 1; and x is an integer between 1 and 10.

In another aspect, the present technology provides a prodrug comprising at least one conjugate of hydrocodone and at least one benzoic acid, a derivative thereof, or a combination thereof.

In yet another aspect, the present technology provides a prodrug comprising at least one conjugate of hydrocodone and at least one heteroaryl carboxylic acid, a derivative thereof, or a combination thereof. In some aspects, the prodrug includes at least one heteroaryl carboxylic acid selected from formula II, formula III or formula IV, wherein formula II, formula III and formula IV are:

wherein X, Y and Z are independently selected from the group consisting of H, O, S, NH and —(CH₂)_(x)—; R¹, R² and R³ are independently selected from the group consisting of H, alkyl, alkoxy, aryl, alkenyl, alkynyl, halo, haloalkyl, alkylaryl, arylalkyl, heterocycle, arylalkoxy, cycloalkyl, cycloalkenyl and cycloalkynyl; o, p, q are independently selected from 0 or 1; and x is an integer from 1 to 10.

In yet another aspect, the present technology provides a prodrug comprising at least one conjugate of hydrocodone and at least one nicotinic acid, a derivative thereof, or a combination thereof.

In some aspects, the prodrug includes an amino benzoate, a hydroxybenzoate, an aminohydroxybenzoate, a derivative thereof, or combination thereof.

In some aspects, at least one conjugate binds reversibly to the opioid receptors of the patient. In some further aspects, at least one conjugate binds reversibly to the opioid receptors of the patient without a CNS depressive effect. In yet another aspect, at least one conjugate prevents or reduces at least one constipatory side effect of unconjugated hydrocodone.

In one aspect, the present technology provides a method for treating a patient having moderate to severe pain, acute or chronic pain, narcotic or opioid abuse; or narcotic or opioid withdrawal. The method may be carried out by orally administering to the patient (human or animal) a pharmaceutically effective amount of a composition comprising acetaminophen and benzoate-hydrocodone hydrochloride. The composition has reduced side effects when compared with unconjugated hydrocodone. In one embodiment, the composition comprises 6.67 mg benzoate-hydrocodone hydrochloride (equivalent to 6.12 mg benzhydrocodone) and 325 mg acetaminophen. In alternative embodiments, the composition comprises 4.45 mg benzoate-hydrocodone hydrochloride (equivalent to 4.08 mg benzhydrocodone) and 325 mg acetaminophen, or 8.90 mg benzoate-hydrocodone hydrochloride (equivalent to 8.16 mg benzhydrocodone) and 325 mg acetaminophen. Other dosages of the present technology are also envisaged, such as 1.67 mg benzoate-hydrocodone hydrochloride (equivalent to 1.53 mg benzhydrocodone) and 81.25 mg acetaminophen, or 2.23 mg benzoate-hydrocodone hydrochloride (equivalent to 2.05 mg benzhydrocodone) and 108.33 mg acetaminophen, or 3.33 mg benzoate-hydrocodone hydrochloride (equivalent to 3.05 mg benzhydrocodone) and 162.5 mg acetaminophen, or 4.45 mg benzoate-hydrocodone hydrochloride (equivalent to 4.08 mg benzhydrocodone) and 216.67 mg acetaminophen.

In another aspect, the present technology provides a method for treating a patient (human or animal) having moderate to severe pain, narcotic or opioid abuse; or narcotic or opioid withdrawal comprising administering to the patient a pharmaceutically effective amount of a composition of a conjugate of hydrocodone wherein the conjugate exhibits lower mean exposure to hydrocodone about more than 53 mg when compared to unconjugated hydrocodone; or has reduced side effects when compared with an equivalent molar amount of unconjugated hydrocodone.

Optionally in any embodiment, the composition may comprise benzoate-hydrocodone hydrochloride and acetaminophen having a molar ratio from 0.001:1 to 1000:1. Optionally in any embodiment, the composition may be a conjugate or a prodrug.

Optionally in any embodiment, the composition may be used to reduce or prevent oral, intranasal or intravenous drug abuse; or to provide oral, intranasal or parenteral drug abuse resistance. Optionally in any embodiment, the composition may exhibit an improved AUC and rate of release of hydrocodone over time when compared to unconjugated hydrocodone over the same time period; exhibits lower exposure to hydrocodone at about more than 53 mg when compared to an equivalent molar amount of unconjugated hydrocodone.

Optionally in any embodiment, the composition may exhibit an improved AUC and rate of release of hydromorphone over time when compared to unconjugated hydrocodone over the same time period, and may also exhibit lower exposure to hydromorphone at about more than 53 mg when compared to an equivalent molar amount of unconjugated hydrocodone.

Optionally in any embodiment, the composition may exhibit a lower maximum peak exposure (C_(max)) to hydrocodone at about more than 53 mg when compared to an equivalent molar amount of unconjugated hydrocodone.

Optionally in any embodiment, the composition may exhibit a lower maximum peak exposure (C_(max)) to hydromorphone at about more than 53 mg when compared to an equivalent molar amount of unconjugated hydrocodone.

Optionally in any embodiment, the composition may be provided in a dosage form selected from the group consisting of: a tablet, a capsule, a caplet, a suppository, a troche, a lozenge, an oral powder, a solution, an oral film, a thin strip, a slurry, and a suspension.

Optionally in any embodiment, the composition may be provided in an amount sufficient to provide a therapeutically bioequivalent AUC for hydrocodone at about lower than 53 mg when compared to an equivalent molar amount of unconjugated hydrocodone.

Optionally in any embodiment, at least one composition may be provided in an amount sufficient to provide a therapeutically bioequivalent AUC and C_(max) for hydrocodone at about lower than 53 mg when compared to an equivalent molar amount of unconjugated hydrocodone.

Optionally in any embodiment, one of the reduced side effects comprises a lower than normal concentration of oxygen in arterial blood of the human or animal patient (hypoxia).

Optionally in any embodiment, one of the reduced side effects comprises respiratory depression in the human or animal patient.

BRIEF DESCRIPTION OF SEVERAL VIEWS OF THE DRAWINGS

FIG. 1. Chemical structures of hydroxybenzoic acids and benzoic acid derivatives for use in the making of the conjugates of the present technology.

FIG. 2. Chemical structures of aminobenzoic acids for use in the making of the conjugates of the present technology.

FIG. 3. Chemical structures of aminohydroxybenzoic acids for use in the making of conjugates of the present technology.

FIG. 4. FIG. 4A is a Table of common hydrocodone products and dosage ranges and FIG. 4B is a Table of common hydrocodone products used in cough syrups.

FIG. 5. PK profile graph of plasma concentrations of hydrocodone released from Bz-HC (benzoate-hydrocodone), YYFFI-HC (Tyr-Tyr-Phe-Phe-Ile-Hydrocodone) and Diglycolate-HC over time upon oral administration in rats.

FIG. 6. PK profile graph of plasma concentrations of active metabolite hydromorphone over time upon oral administration of Bz-HC, YYFFI-HC, and Diglycolate-HC in rats.

FIG. 7. PK profile graph of plasma concentrations of hydrocodone released from Bz-HC and Adipate-HC over time upon intranasal administration in rats.

FIG. 8. PK profile graph of plasma concentrations of active metabolite hydromorphone over time upon intranasal administration of Bz-HC and Adipate-HC in rats.

FIG. 9. PK profile graph of plasma concentrations of hydrocodone released from Bz-HC, Nicotinate-HC and Hydrocodone.BT over time upon oral administration in rats.

FIG. 10. PK profile graph of plasma concentrations of active metabolite hydromorphone over time upon oral administration of Bz-HC, Nicotinate-HC and Hydrocodone.BT in rats.

FIG. 11. PK profile graph of plasma concentrations of hydrocodone released from Bz-HC, 2-ABz-HC and Hydrocodone.BT over time upon oral administration in rats.

FIG. 12. PK profile graph of plasma concentrations of active metabolite hydromorphone over time upon oral administration of Bz-HC, 2-ABz-HC and Hydrocodone.BT in rats.

FIG. 13. Synthesis diagrams of conjugates of hydrocodone. FIG. 13A depicts the synthesis of benzoate hydrocodone. FIG. 13B depicts the synthesis of nicotinate hydrocodone (nicotinic acid). FIG. 13C depicts the synthesis of 2-aminobenzoate hydrocodone. FIG. 13D depicts the synthesis of salicylate hydrocodone.

FIG. 14. PK profile graph of plasma concentrations of intact Bz-HC, active metabolite hydromorphone and of hydrocodone released from Bz-HC over time upon oral administration in rats.

FIG. 15. PK profile graph of plasma concentrations of hydrocodone released from Bz-HC and hydrocodone.BT over time upon oral administration in dogs.

FIG. 16. PK profile graph of plasma concentrations of active metabolite hydromorphone over time upon oral administration of Bz-HC and hydrocodone.BT in dogs.

FIG. 17. PK profile graph of plasma concentrations of intact Bz-HC and of hydrocodone released from Bz-HC over time upon oral administration in dogs.

FIG. 18. PK profile graph of plasma concentrations of intact Bz-HC, active metabolite hydromorphone and of hydrocodone released from Bz-HC over time upon intravenous administration in rats at 0.30 mg/kg.

FIG. 19. PK profile graph of plasma concentrations of hydrocodone released from Bz-HC over time upon oral administration in rats at six different dosages.

FIG. 20. PK profile graph of plasma concentrations of active metabolite hydromorphone over time upon oral administration of Bz-HC in rats at six different dosages.

FIG. 21a . PK profile graph of plasma concentrations of hydrocodone released from Bz HC.HCl/APAP (6.67 mg/325 mg) and HB/APAP over a complete time course upon oral administration of three single doses in recreational drug users.

FIG. 21b . PK profile graph of plasma concentrations of hydrocodone released from Bz-HC.HCl/APAP (6.67 mg/325 mg) and HB/APAP over a first 3 hours of post-dose upon oral administration of three single doses in recreational drug users.

FIG. 22a . PK profile graph of plasma concentrations of hydromorphone released from Bz-HC.HCl/APAP (6.67 mg/325 mg) and HB/APAP over a complete time course upon oral administration of three single doses in recreational drug users.

FIG. 22b . PK profile graph of plasma concentrations of hydromorphone released from Bz-HC.HCl/APAP (6.67 mg/325 mg) and HB/APAP over a first 3 hours of post-dose upon oral administration of three single doses in recreational drug users.

FIG. 23. PK profile graph of plasma concentrations of hydrocodone and hydromorphone released from Bz HC.HCl/APAP (6.67 mg/325 mg) and HB/APAP (7.5 mg/325 mg) after oral administration of a single dose.

DETAILED DESCRIPTION OF THE INVENTION

The present technology provides compositions comprising aryl carboxylic acids chemically conjugated to hydrocodone (morphinan-6-one, 4,5-alpha-epoxy-3-methoxy-17-methyl) to form novel prodrugs and compositions of hydrocodone. In some embodiments, the chemical bond between these two moieties can be established by reacting the C-6 enol tautomer of hydrocodone with the activated carboxylic acid function of an aryl carboxylic acid thereby creating an enol-ester conjugate.

The use of “opioid” is meant to include any drug that activates the opioid receptors found in the brain, spinal cord and gut. There are four broad classes of opioids: naturally occurring opium alkaloids, such as morphine (the prototypical opioid) codeine, and thebaine; endogenous opioid peptides, such as endorphins; semi-synthetics such as heroine, oxycodone and hydrocodone that are produced by modifying natural opium alkaloids (opiates) and have similar chemical structures; and pure synthetics such as fentanyl and methadone that are not produced from opium and may have very different chemical structures than the opium alkaloids. Additional examples of opioids are hydromorphone, oxymorphone, methadone, levorphanol, dihydrocodeine, meperidine, diphenoxylate, sufentanil, alfentanil, propoxyphene, pentazocine, nalbuphine, butorphanol, buprenorphine, meptazinol, dezocine, and pharmaceutically acceptable salts thereof.

The use of “hydrocodone” is meant to include a semisynthetic narcotic analgesic and antitussive prepared from codeine with multiple actions qualitatively similar to those of codeine. It is commonly used for the relief of moderate to moderately severe pain. Trade names include Anexsia™, Hycodan™, Hycomine™, Lorcet™, Lortab™, Norco™, Tussionex™, Tylox™, and Vicodin™. Other salt forms of hydrocodone, such as hydrocodone bitartrate and hydrocodone polistirex, are encompassed by the present technology.

The use of “prodrug” is meant to include pharmacologically inactive substances that are a modified form of a pharmacologically active drug to which it is converted in the body by, for example, enzymatic action, such as during first pass metabolism.

As used herein, the following conventional unit abbreviations and terms are used as follows: “pg” refers to picogram, “ng” refers to nanogram, “μg” refers to microgram, “mg” refers to milligram, “g” refers to gram, “kg” refers to kilogram, “mL” refers to milliliter, “h” refers to hour and “t” refers to time.

As used herein, the following conventional pharmacokinetic abbreviations and terms are used as follows: “PK” refers to pharmacokinetics, “AUC_(0-t)” refers to area under the plasma concentration-time curve to the last time with a concentration≥LLOQ, “AUC_(inf)” refers to the area under the plasma concentration-time curve to infinity, “C_(max)” refers to the maximum plasma concentration, “T_(max)” refers to the time of maximum plasma concentration, and “t_(1/2)” refers to the elimination half-life.

As used herein, the following conventional statistical abbreviations and terms are used as follows: “LLOQ” refers to the validated lower limit of the bioanalytical method, “ANOVA” refers to Analysis of Variance and “p” refers to probability.

As used herein, “APAP” refers to acetaminophen.

As used herein, “LC/MS/MS” refers to liquid chromatography/mass spectrometry/mass spectrometry.

As used herein, “patient” refers to a human or animal patient.

Some embodiments of the present technology provide carboxylic acids conjugated to hydrocodone, where the carboxylic acid group is directly attached to the aryl moiety. Carboxylic acids directly attached to the aryl moiety include benzoates and heteroaryl carboxylic acids.

Some embodiments of the present technology provide at least one conjugate of hydrocodone and at least one benzoic acid or benzoic acid derivative, a salt thereof, or a combination thereof. Benzoates are common in nature and include, for example but are not limited to, aminobenzoates (e.g., anthranilic acid analogs such as fenamates), aminohydroxybenzoates and hydroxybenzoates (e.g., salicylic acid analogs).

The general structure of benzoic acid and benzoic acid derivatives of the present technology is:

where X, Y and Z can be independently any combination of H, O, S, NH or —(CH₂)—; R¹, R² and R³ can be independently any of the following: H, alkyl, alkoxy, aryl, alkenyl, alkynyl, halo, haloalkyl, alkylaryl, arylalkyl, heterocycle, arylalkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl, and o, p, q can be independently either 0 or 1.

Suitable hydroxyobenzoic acids can be found in FIG. 1 and include, but are not limited to, benzoic acid, salicylic acid, acetylsalicylic acid (aspirin), 3-hydroxybenzoic acid, 4-hydroxybenzoic acid, 6-methylsalicylic acid, o,m,p-cresotinic acid, anacardic acids, 4,5-dimethylsalicylic acid, o,m,p-thymotic acid, diflusinal, o,m,p-anisic acid, 2,3-dihydroxybenzoic acid (2,3-DHB), α,β,γ-resorcylic acid, protocatechuic acid, gentisic acid, piperonylic acid, 3-methoxysalicylic acid, 4-methoxysalicylic acid, 5-methoxysalicylic acid, 6-methoxysalicylic acid, 3-hydroxy-2-methoxybenzoic acid, 4-hydroxy-2-methoxybenzoic acid, 5-hydroxy-2-methoxybenzoic acid, vanillic acid, isovanillic acid, 5-hydroxy-3-methoxybenzoic acid, 2,3-dimethoxybenzoic acid, 2,4-dimethoxybenzoic acid, 2,5-dimethoxybenzoic acid, 2,6-dimethoxybenzoic acid, veratric acid (3,4-dimethoxybenzoic acid), 3,5-dimethoxybenzoic acid, gallic acid, 2,3,4-trihydroxybenzoic acid, 2,3,6-trihydroxybenzoic acid, 2,4,5-trihydroxybenzoic acid, 3-O-methylgallic acid (3-OMGA), 4-O-methylgallic acid (4-OMGA), 3,4-O-dimethylgallic acid, syringic acid, 3,4,5-trimethoxybenzoic acid.

Suitable aminobenzoic acids are shown in FIG. 2 and include, but are not limited to, anthranilic acid, 3-aminobenzoic acid, 4,5-dimethylanthranilic acid, N-methylanthranilic acid, N-acetylanthranilic acid, fenamic acids (e.g., tolfenamic acid, mefenamic acid, flufenamic acid), 2,4-diaminobenzoic acid (2,4-DABA), 2-acetylamino-4-aminobenzoic acid, 4-acetylamino-2-aminobenzoic acid, 2,4-diacetylaminobenzoic acid.

Suitable aminohydroxybenzoic acids include, but are not limited to, 4-Aminosalicylic acid, 3-hydroxyanthranilic acid, 3-methoxyanthranilic acid.

In some embodiments, the composition includes a benzoate conjugate comprising at least one hydrocodone conjugated to at least one benzoic acid or benzoic acid derivative, salt thereof or combination thereof, including polymorphs thereof. [any value of adding in the term isomer?]

In some embodiments, the benzoates include numerous benzoic acid analogs, benzoate derivatives with hydroxyl or amino groups or a combination of both. The hydroxyl and amino functions may be present in their free form or capped with another chemical moiety, preferably but not limited to methyl or acetyl groups. The phenyl ring may have additional substituents, but the total number of substituents can be four or less, three or less, or two or less.

In another embodiment, the prodrug or conjugate composition of the present technology is benzoate-hydrocodone, which has the structure:

In yet another embodiment, the present technology provides a prodrug or composition comprising at least one conjugate of hydrocodone and at least one heteroaryl carboxylic acid, a derivative thereof, or a combination thereof. The heteroaryl carboxylic acid can be selected from formula II, formula III or formula IV where formula II, formula III and formula IV are:

For these formulas, X, Y and Z are independently selected from the group consisting of H, O, S, NH and —(CH₂)_(x)—; R¹, R² and R³ are independently selected from the group consisting of H, alkyl, alkoxy, aryl, alkenyl, alkynyl, halo, haloalkyl, alkylaryl, arylalkyl, heterocycle, arylalkoxy, cycloalkyl, cycloalkenyl and cycloalkynyl; o, p, q are independently selected from 0 or 1; and x is an integer from 1 to 10.

In some embodiments, the carboxy group of the aryl carboxylic acids can be attached directly to the aromatic ring. The present technology includes both carbon-only aryl groups and aryl groups with heteroatoms (heteroaryl). The aryl or heteroaryl group which is connected directly to the carboxyl function can be a 6-membered ring and contains no or one heteroatom. In some embodiments, the additional substituted or unsubstituted aromatic or aliphatic rings can be fused to this 6-membered aryl or heteroaryl moiety. In some embodiments, the aryl carboxylic acids may have only one free carboxylic acid group and the total number of phenyl substituents on the 6-membered ring should be four or less, for example, 4, 3, 2 or 1.

In some embodiments of the present technology, depending on the individual aryl carboxylic acid that is connected to hydrocodone, the conjugate of hydrocodone can have a neutral, free acid, free base, or various pharmaceutically acceptable anionic or cationic salt forms or salt mixtures with any ratio between positive and negative components. These salt forms include, but are not limited to: acetate, L-aspartate, besylate, bicarbonate, carbonate, D-camsylate, L-camsylate, citrate, edisylate, fumarate, gluconate, hydrobromide/bromide, hydrochloride/chloride, D-lactate, L-lactate, D,L-lactate, D,L-malate, L-malate, mesylate, pamoate, phosphate, succinate, sulfate, D-tartrate, L-tartrate, D,L-tartrate, meso-tartrate, benzoate, gluceptate, D-glucuronate, hybenzate, isethionate, malonate, methylsulfate, 2-napsylate, nicotinate, nitrate, orotate, stearate, tosylate, acefyllinate, aceturate, aminosalicylate, ascorbate, borate, butyrate, camphorate, camphocarbonate, decanoate, hexanoate, cholate, cypionate, dichloroacetate, edentate, ethyl sulfate, furate, fusidate, galactarate (mucate), galacturonate, gallate, gentisate, glutamate, glutarate, glycerophosphate, heptanoate (enanthate), hydroxybenzoate, hippurate, phenylpropionate, iodide, xinafoate, lactobionate, laurate, maleate, mandelate, methanesulfonate, myristate, napadisilate, oleate, oxalate, palmitate, picrate, pivalate, propionate, pyrophosphate, salicylate, salicylsulfate, sulfosalicylate, tannate, terephthalate, thiosalicylate, tribrophenate, valerate, valproate, adipate, 4-acetamidobenzoate, camsylate, octanoate, estolate, esylate, glycolate, thiocyanate, and undecylenate.

In one embodiment, the prodrug of the present technology is benzhydrocodone hydrochloride, chemically known as 6,7-didehydro-4,5a-epoxy-3-methoxy-17-methylmorphinan-6-yl-benzoate hydrochloride. Benzhydrocodone hydrochloride has the molecular formula C₂₅H₂₆ClNO₄, a molecular weight of 439.93 g/mol, and has the following chemical structure:

For the present technology, a suitable conjugate of hydrocodone includes nicotinate-hydrocodone, which has the following structure:

Some embodiments of the present technology are believed to provide a conjugate of hydrocodone that is broken down in vivo either enzymatically or otherwise, releasing the active hydrocodone and the respective aryl carboxylic acid or metabolites thereof. The aryl carboxylic acids used in the conjugates of the present technology are non-toxic at the given dosing levels and are preferably known drugs, natural products, metabolites, or GRAS (Generally Regarded As Safe) compounds (e.g., preservatives, dyes, flavors, etc.) or non-toxic mimetics thereof. For example, when benzhydrocodone is broken down, the active hydrocodone and benzoic acid are released. The benzoic acid is metabolized and believed to be naturally excreted.

Compounds, compositions and methods of the present technology provide reduced potential for overdose, reduced potential for abuse or addiction and/or improve hydrocodone's characteristics with regard to high toxicities or suboptimal release profiles. Without wishing to be limited to the below theory, the present inventors believe that overdose protection may occur due to the conjugates being exposed to different enzymes and/or metabolic pathways by oral administration where the conjugate is exposed through the gut and first-pass metabolism as opposed to exposure to enzymes in the circulation or mucosal membranes which limits the ability of the hydrocodone from being released from the conjugate. Therefore, abuse resistance is provided by limiting the “rush” or “high” available from the active hydrocodone released by the prodrug and limiting the effectiveness of alternative routes of administration.

The compositions of the present technology preferably have no or a substantially decreased pharmacological activity when administered through injection or intranasal routes of administration. However, they remain orally bioavailable. Again, not wanting to be bound by any particular theory, the bioavailability can be a result of the hydrolysis of the chemical linkage (i.e., a covalent linkage such as a covalent bond) following oral administration. In at least one embodiment, release of hydrocodone is reduced when the composition of the present technology is delivered by parenteral routes.

For example, in one embodiment, the composition of the present technology maintains its effectiveness and abuse resistance following the crushing of the tablet, capsule or other oral dosage form. In contrast, from parental non-conjugated (or “unconjugated”) forms of hydrocodone, the hydrocodone is released immediately following crushing allowing the content of the crushed tablet to be used by injection or snorting producing the “rush” effect sought by addicts.

In some embodiments of the present technology, the conjugates of hydrocodone can be given orally to an animal or human patient, and, upon administration, release the active hydrocodone by being hydrolyzed in the body. Not to be bound by any particular theory, it is believed that since the aryl carboxylic acids are naturally occurring metabolites or mimetics thereof or pharmaceutically active compounds, these conjugates can be easily recognized by physiological systems resulting in hydrolysis and release of hydrocodone. The conjugates themselves have either no or limited pharmacological activity as a conjugate and consequently may follow a metabolic pathway that differs from the parent drug.

In some embodiments of the present technology, the choice of suitable aryl carboxylic acids (“ligands”) to conjugate to hydrocodone determines the release of hydrocodone into the systemic circulation and can be controlled even when the conjugate is administered via routes other than oral. In one embodiment, the modified hydrocodone would release hydrocodone similar to free or unmodified hydrocodone. In another embodiment, the conjugated hydrocodone releases hydrocodone in a controlled or sustained form. In some embodiments, this controlled release can alleviate certain side-effects and improve upon the safety profile of the parent drug. These side-effects may include, but are not limited to, anxiety, bruising, constipation, decreased appetite, difficulty breathing, dizziness, drowsiness, dry throat, diarrhea, headache, nausea, stomach cramps, stomach pain, vomiting. In another embodiment, the conjugated hydrocodone would selectively allow hydrocodone to be metabolized to hydromorphone. In some embodiments, these conjugates can be used for pain relief, such as moderate to severe pain relief.

Hydrocodone and other opioids are also highly addictive and prone to substance abuse. Recreational drug abuse of opioids is a common problem and usually begins with oral doses taken with the purpose of achieving euphoria (“rush”, “high”). Over time the drug abuser often increases the oral dosages to attain more powerful “highs” or to compensate for heightened opioid tolerance. This behavior can escalate and result in exploring of other routes of administration such as intranasal (“snorting”) and intravenous (“shooting”).

In some embodiments of the present technology, the hydrocodone that is conjugated with a suitable aryl carboxylic acid ligand does not result in rapid spikes in plasma concentrations after oral administration that is sought by a potential drug abuser. In some embodiments, hydrocodone released from these conjugates has a delayed T_(max) and possibly lower C_(max) than the unconjugated hydrocodone. Not to be bound by any particular theory, it is believed that the conjugates of the present technology, when taken orally or by other non-oral routes, do not provide the feeling of a “rush” even when taken at higher doses, but still maintain pain relief.

Additionally, in some embodiments, hydrocodone conjugated with appropriate ligands of the present technology is not hydrolyzed efficiently when administered via non-oral routes. As a result, these conjugates do not generate as high plasma or blood concentrations of released hydrocodone when injected or snorted compared to free hydrocodone administered through these routes.

In some embodiments, the conjugates of the present technology, since they consist of covalently bound hydrocodone, are not able to be physically manipulated to release the hydrocodone opioid from the conjugated hydrocodone by methods, for example, of grinding up or crushing of solid forms. Further, the conjugates of the present technology exhibits resistance to chemical hydrolysis under conditions a potential drug abuser may apply to “extract” the active portion of the molecule, for example, by boiling, or acidic or basic solution treatment of the conjugate.

The compositions and prodrugs of the present technology can be oral dosage forms. These dosage forms include but are not limited to tablet, capsule, caplet, troche, lozenge, powder, suspension, syrup, solution or oral thin film (OTF). Preferred oral administration forms are capsule, tablet, solutions and OTF.

Solid dosage forms can include, but are not limited to, the following types of excipients: antiadherents, binders, coatings, disintegrants, fillers, flavors and colors, glidants, lubricants, preservatives, sorbents and sweeteners.

Oral formulations of the present technology can also be included in a solution or a suspension in an aqueous liquid or a non-aqueous liquid. The formulation can be an emulsion, such as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The oils can be administered by adding the purified and sterilized liquids to a prepared enteral formula, which is then placed in the feeding tube of a patient who is unable to swallow.

Soft gel or soft gelatin capsules may be prepared, for example by dispersing the formulation in an appropriate vehicle (vegetable oils are commonly used) to form a high viscosity mixture. This mixture is then encapsulated with a gelatin based film using technology and machinery known to those in the soft gel industry. The individual units so formed are then dried to constant weight.

Chewable tablets, for example, may be prepared by mixing the formulations with excipients designed to form a relatively soft, flavored, tablet dosage form that is intended to be chewed rather than swallowed. Conventional tablet machinery and procedures, for example, direct compression and granulation, i.e., or slugging, before compression, can be utilized. Those individuals involved in pharmaceutical solid dosage form production are versed in the processes and the machinery used, as the chewable dosage form is a very common dosage form in the pharmaceutical industry.

Film coated tablets, for example may be prepared by coating tablets using techniques such as rotating pan coating methods or air suspension methods to deposit a contiguous film layer on a tablet.

Compressed tablets, for example may be prepared by mixing the formulation with excipients intended to add binding qualities as well as disintegration qualities, among others. The mixture is either directly compressed or granulated then compressed using methods and machinery known to those in the industry. The resultant compressed tablet dosage units are then packaged according to market need, for example, in unit dose, rolls, bulk bottles, blister packs, etc.

The present technology also contemplates the use of biologically-acceptable carriers which may be prepared from a wide range of materials. Without being limited to, such materials include diluents, binders and adhesives, lubricants, plasticizers, disintegrants, colorants, bulking substances, flavorings, sweeteners and miscellaneous materials such as buffers and adsorbents in order to prepare a particular medicated composition.

Binders may be selected from a wide range of materials such as hydroxypropylmethylcellulose, ethylcellulose, or other suitable cellulose derivatives, povidone, acrylic and methacrylic acid co-polymers, pharmaceutical glaze, gums, milk derivatives, such as whey, starches, and derivatives, as well as other conventional binders known to persons working in the art. Exemplary non-limiting solvents are water, ethanol, isopropyl alcohol, methylene chloride or mixtures and combinations thereof. Exemplary non-limiting bulking substances include sugar, lactose, gelatin, starch, and silicon dioxide.

It should be understood that in addition to the ingredients particularly mentioned above, the formulations of the present technology can include other suitable agents such as flavoring agents, preservatives and antioxidants. Such antioxidants would be food acceptable and could include vitamin E, carotene, BHT or other antioxidants.

Other compounds which may be included by admixture are, for example, medically inert ingredients, e.g., solid and liquid diluents, such as lactose, dextrose, saccharose, cellulose, starch or calcium phosphate for tablets or capsules, olive oil or ethyl oleate for soft capsules and water or vegetable oil for suspensions or emulsions; lubricating agents such as silica, talc, stearic acid, magnesium or calcium stearate and/or polyethylene glycols; gelling agents such as colloidal clays; thickening agents such as gum tragacanth or sodium alginate, binding agents such as starches, arabic gums, gelatin, methylcellulose, carboxymethylcellulose or polyvinylpyrrolidone; disintegrating agents such as starch, alginic acid, alginates or sodium starch glycolate; effervescing mixtures; dyestuff; sweeteners; wetting agents such as lecithin, polysorbates or laurylsulfates; and other therapeutically acceptable accessory ingredients, such as humectants, preservatives, buffers and antioxidants, which are known additives for such formulations.

For oral administration, fine powders or granules containing diluting, dispersing and/or surface-active agents may be presented in a draught, in water or a syrup, in capsules or sachets in the dry state, in a non-aqueous suspension wherein suspending agents may be included, or in a suspension in water or a syrup. Where desirable, flavoring, preserving, suspending, thickening or emulsifying agents can be included.

Liquid dispersions for oral administration may be syrups, emulsions or suspensions. The syrups may contain as carrier, for example, saccharose or saccharose with glycerol and/or mannitol and/or sorbitol, among others. In particular a syrup for diabetic patients can contain as carriers only products, for example sorbitol, which do not metabolize to glucose or which metabolize only a very small amount to glucose. The suspensions and the emulsions may contain a carrier, for example a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose or polyvinyl alcohol, among others.

Current approved formulations of hydrocodone are combination therapies of hydrocodone and one or more other non-narcotic active ingredient depending on intended indication. Examples of these active pharmaceuticals include, but are not limited to, acetaminophen, phenylpropanolamine, homatropine, ibuprofen, aspirin, pheniramine, chlorpheniramine, phenylephrine, pseudoephedrine, pyrilamine and guaifenesin. The conjugated hydrocodone of the present technology can be formulated with one or a combination of these or other active substances or as standalone active ingredient without any other actives.

Certain formulations of the compounds, products, compositions, conjugates and prodrugs of the current technology comprise Bz-HC.HCl, bulking agents and diluents, such as, for example, microcrystalline cellulose and crospovidone, disintegrants, such as, for example, starch 1500 G, binders, such as, for example, povidone (e.g. povidone K30), lubricants, such as, for example, stearic acid, and granulation solvents, such as, for example, purified water. Such formulations of the current technology may also include additional pharmaceutical actives, such as, for example, acetaminophen.

The amounts and relative percentages of the different active and inactive components of the formulations of the current technology can be modified, selected and adjusted in order to arrive at desirable formulations, dosages and dosage forms for therapeutic administration of the compounds, products, compositions, conjugates and prodrugs of the current technology. Representative examples of oral dosage formulations of the present technology are presented in Table 1.

TABLE 1 Component and Quality Standard 4.45 mg/325 mg 6.67 mg/325 mg 8.90 mg/325. mg (and Grade, if Quantity Quantity Quantity applicable) Function mg/tablet % w/w mg/tablet % w/w mg/tablet % w/w Bz-HC•HCl ^(a,) Professed Active 4.45 0.81 6.67 1.21 8.90 1.62 Acetaminophen USP Active 325.0 59.09 325.0 59.09 325.0 59.09 Excipients* Inactive 220.55 40.10 218.33 39.70 216.1 39.29 Total (mg/tablet) 550.0 100.0 550.0 100.0 550.0 100.0 *Excipients are one or more of the following: crospovidone, microcrystalline cellulose, pregelatinized starch, Povidone K30, and stearic acid.

A suitable dosage form for the dosage formulation in Table 1 can be a tablet having, for example, a capsule shape.

The conjugate compositions or prodrugs may be used in methods of treating a patient having a disease, disorder or condition requiring or mediated by binding or inhibiting binding of an opioid to the opioid receptors of the patient. Treatment comprises orally administering to the patient a pharmaceutically effective amount of at least one conjugate of hydrocodone as described in the present technology. The conjugate can exhibit a slower rate of release over time and AUC when compared to an equivalent molar amount of unconjugated hydrocodone. In other embodiments, at least one conjugate can exhibit less variability in the oral PK profile when compared to unconjugated hydrocodone.

In other embodiments, at least one conjugate is provided in an amount sufficient to provide a therapeutically bioequivalent AUC (area under the curve) when compared to a molar equivalent amount of unconjugated hydrocodone. In further embodiments, the conjugate is provided in an amount sufficient to provide a therapeutically bioequivalent AUC when compared to unconjugated hydrocodone but has a lower C_(max) (peak concentration) in plasma or does not provide an equivalent C_(max) in plasma concentrations. In some aspects, the conjugate is provided in an amount sufficient to provide a therapeutically bioequivalent C_(max) when compared to unconjugated hydrocodone.

Suitable diseases, disorders or conditions that can be treated by the prodrugs or compositions of the present technology are narcotic addiction or drug addiction and/or pain requiring an opioid. In some embodiments, compositions of the present technology can be used for the treatment, and/or management, of acute pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. In some embodiments, pain requiring an opioid may be acute or chronic pain. Acute pain is pain lasting from 0 to about 1 week, alternatively from 0 to about 2 weeks, alternatively from 0 to about 3 weeks, alternatively from 0 to about 4 weeks, alternatively from 0 to about 1 month, alternatively from 0 to about 3 months, alternatively from 0 to about 6 months. Chronic pain is pain lasting more than about 2 weeks, alternatively more than 3 weeks, alternatively more than 4 weeks, alternatively more than 2 months, alternatively more than 3 months, alternatively more than 6 months. In some embodiments, compositions of the present technology can treat pain lasting for no more than 14 days, alternatively pain lasting for 1 month, alternatively pain lasting for 2 months, alternatively pain lasting for 3 months, alternatively pain lasting for 6 months.

Dosages for the conjugates of the present technology depend on their molecular weight and the respective weight-percentage of hydrocodone as part of the whole conjugate, and therefore can be higher than the dosages of free hydrocodone. Dosages can be calculated based on the strengths of dosages of hydrocodone bitartrate which range between 2.5 mg and 15 mg per dose. Dose conversion from hydrocodone bitartrate to hydrocodone prodrug can be performed using the following formula: dose(HC prodrug/conjugate)=[dose(HC bitartrate)×(molecular weight(HC prodrug/conjugate)/494.49)]/proportion of hydrocodone released from prodrug/conjugate

HC: Hydrocodone

Suitable dosages of the conjugated hydrocodone of the present technology include, but are not limited to, formulations including from about 0.5 mg or higher, alternatively from about 2.5 mg or higher, alternatively from about 5.0 mg or higher, alternatively from about 7.5 mg or higher, alternatively from about 10 mg or higher, alternatively from about 20 mg or higher, alternatively from about 30 mg or higher, alternatively from about 40 mg or higher, alternatively from about 50 mg or higher, alternatively from about 60 mg or higher, alternatively from about 70 mg or higher, alternatively from about 80 mg or higher, alternatively from about 90 mg or higher, alternatively from about 100 mg or higher, and include any additional increments thereof, for example, 0.1, 0.2, 0.25, 0.3, 0.4, 0.5, 0.6, 0.7, 0.75, 0.8, 0.9 or 1.0 mg and multiplied factors thereof, (e.g., ×1, ×2, ×2.5, ×5, ×10, ×100, etc). The present technology also includes dosage formulations including currently approved formulations of hydrocodone (See FIG. 4), where the dosage can be calculated using the above-noted formula determined by the amount of hydrocodone bitartrate. The present technology provides for dosage forms formulated as a single therapy or as a combination therapy with other API's (FIG. 4).

In one embodiment, the present technology provides a combination formulation comprising 6.12 mg benzhydrocodone (equivalent to 4.54 mg hydrocodone or 7.5 mg hydrocodone bitartrate), and 325 mg acetaminophen. The combination formulation can comprise benzhydrocodone in the form of benzhydrocodone hydrochloride (6.67 mg) having the following chemical structure:

and acetaminophen (325 mg) having the following chemical structure:

The combination formulation can further comprise additional components, such as one or more excipients selected from crospovidone, microcrystalline cellulose, pregelatinized starch, povidone (for example Povidone K30), and stearic acid. In a particular embodiment, the formulation comprises crospovidone, microcrystalline cellulose, pregelatinized starch, Povidone K30, and stearic acid as additional components. The combination formulation can be formulated into capsule-shaped, immediate release tablets for oral administration for the short-term (no more than 14 days) management of acute pain. Oral administration can be 1 or 2 tablets (6.12 mg benzhydrocodone/325 mg acetaminophen per tablet) every 4 to 6 hours as needed for pain management, not exceeding 12 tablets in a 24-hour period. For example, oral administration of the immediate release tablets can be up to 12 tablets, alternatively up to 10 tablets, alternatively up to 8 tablets, alternatively up to 6 tablets, alternatively up to 4 tablets in a 24-hour period for the treatment of pain, such as acute pain or chronic pain.

In some embodiments, the present technology provides compositions comprising from about 1.5 mg to about 54 mg benzhydrocodone hydrochloride, and optionally about 80 mg to about 350 mg acetaminophen. For example, compositions of the present technology can comprise about 3.33 mg, about 4.45 mg, about 8.90 mg, about 13.34 mg, about 26.68 mg, or about 53.36 mg benzhydrocodone hydrochloride. Optionally, the compositions can comprise about 150 mg, about 162 mg, about 200 mg, about 216.67 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg or about 350 mg acetaminophen.

In specific embodiments of the present technology, the compositions comprise combination formulations of benzhydrocodone hydrochloride and acetaminophen comprising about 1.67 mg benzoate-hydrocodone hydrochloride (equivalent to 1.53 mg benzhydrocodone) and about 81.25 mg acetaminophen, or about 2.23 mg benzoate-hydrocodone hydrochloride (equivalent to 2.05 mg benzhydrocodone) and about 108.33 mg acetaminophen, about 3.33 mg benzhydrocodone hydrochloride (equivalent to 3.05 mg benzhydrocodone) and about 162 mg acetaminophen, alternatively about 4.45 mg benzhydrocodone hydrochloride (equivalent to 4.08 mg benzhydrocodone) and about 216.67 mg acetaminophen, alternatively about 4.45 mg benzhydrocodone hydrochloride (equivalent to 4.08 mg benzhydrocodone) and about 325 mg acetaminophen, alternatively, about 4.45 mg benzhydrocodone hydrochloride (equivalent to 4.08 mg benzhydrocodone) and about 350 mg acetaminophen, alternatively about 8.90 mg benzhydrocodone hydrochloride (equivalent to 8.16 mg benzhydrocodone) and about 325 mg acetaminophen, alternatively about 8.90 mg benzhydrocodone hydrochloride (equivalent to 8.16 mg benzhydrocodone) and about 350 mg acetaminophen, alternatively 13.34 mg benzhydrocodone hydrochloride (equivalent to 12.24 mg benzhydrocodone) and 325 mg acetaminophen, alternatively 26.62 mg benzhydrocodone hydrochloride (equivalent to 24.48 mg benzhydrocodone) and 325 mg acetaminophen, alternatively 53.36 mg benzhydrocodone hydrochloride (equivalent to 48.96 mg benzhydrocodone) and 325 mg acetaminophen. It will be appreciated by one skilled in the art that different amounts (strengths) of benzhydrocodone hydrochloride in the combination formulation may require different doses, such as a dose of 1 to 3 tablets, alternatively 1 to 2 tablets, alternatively 1 to 1.5 tablets, alternatively, 1 tablet, different frequencies of oral administration, such as 3 to 4 hours, alternatively 4 to 6 hours, alternatively 6 to 8 hours, alternatively 8 to 10 hours, and/or different total amounts of benzhydrocodone hydrochloride in a 24 hour period, such as up to 12 tablets in a 24 hour period, alternatively up to 10 tablets, alternatively up to 9 tablets, alternatively up to 8 tablets, alternatively up to 6 tablets, alternatively up to 4 tablets in a 24 hour period for the treatment of pain, such as moderate to severe pain, moderate to moderately severe pain, acute or chronic pain, acute moderate to severe pain, chronic moderate to severe pain, or severe pain.

It should also be appreciated that the doses could be in other forms, such as a liquid. Optionally, the liquid composition provides dose units for oral administration in pediatric or adult patients of 0.12 mg of benzhydrocodone hydrochloride and 5.85 mg of acetaminophen per 1 kg bodyweight.

In some embodiments, tablets comprising 4.45 mg benzhydrocodone hydrochloride and 325 mg acetaminophen could be orally administered at 1 to 2 tablets every 4 to 6 hours, preferably not to exceed 12 tablets in a 24 hour period for the treatment of pain. Tablets comprising 8.90 mg benzhydrocodone hydrochloride and 325 mg acetaminophen could be orally administered at 1 to 2 tablets, alternatively 1 to 1.5 tablets, alternatively 1 tablet every 4 to 6 hours, preferably not to exceed 12 tablets, alternatively 9 tablets, alternatively 6 tablets in a 24 hour period, and tablets comprising 13.34 mg benzhydrocodone hydrochloride could be orally administered at 1 to 2 tablets, alternatively 1 to 1.5 tablets, alternatively 1 tablet every 4 to 6 hours, alternatively 6 to 8 hours, alternatively 8-10 hours, preferably not exceeding 6 tablets in a 24 hour period for the treatment of pain. In some embodiments, for the treatment of severe or acute pain, compositions of the present technology can comprise 26.68 mg benzhydrocodone hydrochloride and 325 mg acetaminophen, and be orally administered at 1 tablet every 4 to 6 hours, alternatively 6 to 8 hours, alternatively 8 to hours, not to exceed 3 tablets in a 24 hour period. Alternatively, in some embodiments, compositions of the present technology can comprise 53.36 mg benzhydrocodone hydrochloride and, optionally, 325 mg acetaminophen, and be orally administered at 1 tablet every 4 to 6 hours, alternatively 6 to 8 hours, alternatively 8 to 10 hours, preferably not to exceed 2 tablets in a 24 hour period, for the treatment of severe or acute pain.

Combination formulations of the present technology can also be formulated for pediatric patients. For example, pediatric formulations can comprise about 3.33 mg benzhydrocodone hydrochloride (equivalent to 3.05 mg benzhydrocodone) and about 162 mg acetaminophen, alternatively about 4.45 mg benzhydrocodone hydrochloride (equivalent to 4.08 mg benzhydrocodone) and about 216.67 mg acetaminophen, alternatively about 6.67 mg benzhydrocodone hydrochloride (equivalent to 6.12 mg benzhydrocodone) and about 325 mg acetaminophen in tablet or liquid form. In one embodiment, the pediatric formulation could be 6.67 mg benzhydrocodone hydrochloride and 325 mg acetaminophen orally administered at 15 ml every 3 to 4, alternatively every 4 to 6 hours.

The conjugates of hydrocodone with derivatives of benzoic acid or nicotinic acid of the present technology have a number of advantages including, but not limited to, a reduced patient variability of plasma concentrations of hydrocodone or hydromorphone when compared to free hydrocodone, reduced drug abuse potential, reduced risk of chemical or physical manipulation resulting in full dosage of hydrocodone released, improved dosage forms through covalent linkage to carboxylic acids or derivatives thereof, increased or decreased metabolism of hydrocodone to hydromorphone and/or decreased side-effects other than drug abuse.

Hydrocodone is a narcotic analgesic, which acts as weak agonist at opioid receptors in the central nervous system (CNS). It primarily affects the μ (mu) receptor (OP3), but also exhibits agonist activity at the δ (delta) receptor (OP1) and κ (kappa) receptor (OP2). Additionally, hydrocodone displays antitussive properties by suppressing the cough reflex in the medullary cough center of the brain.

Side effects of opioid analgesics include gastrointestinal dysfunction caused by the opioids binding to the mu (μ) receptors present in the gastrointestinal tract. The side-effects in the stomach include a reduction in the secretion of hydrochloric acid, decreased gastric motility, thus prolonging gastric emptying time, which can result in esophageal reflux. Passage of the gastric contents through the duodenum may be delayed by as much as 12 hours, and the absorption of orally administered drugs is retarded. In the small intestines the opioid analgesics diminish biliary, pancreatic and intestinal secretions and delay digestion of food in the small intestine. Propulsive peristaltic waves in the colon are diminished or abolished after administration of opioids, and tone is increased to the point of spasm. The resulting delay in the passage of bowel contents causes considerable desiccation of the feces, which, in turn retards their advance through the colon. These actions, combined with inattention to the normal sensory stimuli for defecation reflex due to the central actions of the drug, contribute to opioid-induced constipation.

Hydrocodone is used for the treatment of moderate to moderately severe pain and for inhibition of cough (especially dry, nonproductive cough). The prodrugs of the present technology may be administered for the relief of pain or cough depression or for the treatment of any condition that may require the blocking of opioid receptors.

The conjugates of the present technology can provide a decrease in side effects of the opioid analgesic, including reduced or inhibited constipatory effects.

The present technology also provides a method of synthesis for the preparation of the conjugated hydrocodone of the present technology. In one embodiment, the synthesis of the present technology includes the steps of:

-   -   1. Protection of the ligand, if necessary;     -   2. Activation of the ligand carboxylic acid group, if not         already in activated form;     -   3. Addition of the activated ligand to hydrocodone or vice versa         in the presence of base; and     -   4. Removal of ligand protecting groups, if applicable.

If the aryl carboxylic acid contains any additional reactive functional groups that may interfere with the coupling to hydrocodone, it may be necessary to first attach one or more protecting groups. Any suitable protecting group may be used depending on the type of functional group and reaction conditions. Some protecting group examples are: acetyl (Ac), β-methoxyethoxymethyl ether (MEM), methoxymethyl ether (MOM), p-methoxybenzyl ether (PMB), trimethylsilyl (TMS), tert.-butyldimethylsilyl (TBDPS), triisopropylsilyl (TIPS), carbobenzyloxy (Cbz), p-methoxybenzyl carbonyl (Moz), tert.-butyloxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl (Fmoc), benzyl (Bn), p-methoxybenzyl (MPM), tosyl (Ts). Temporary formation of acetals or ketals from carbonyl functions may also be appropriate.

The carboxylic acid group of the ligands should be activated in order to react with hydrocodone and to generate appreciable amounts of conjugate. This activation can be accomplished in numerous ways by a variety of coupling agents known to one skilled in the art. Examples of such coupling agents are: N,N′-dicyclohexylcarbodiimide (DCC), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (EDCI), N,N′-diisopropylcarbodiimide (DIC), 1,1′-carbonyldiimidazole (CDI) or other carbodiimides; (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), bromotripyrrolidinophosphonium hexafluorophosphate (PyBroP), (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP) or other phosphonium-based reagents; O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU), fluoro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (TFFH), N,N,N′,N′-tetramethyl-O—(N-succinimidyl)uronium tetrafluoroborate (TSTU) or other aminium-based reagents. The aryl carboxylic acid can also be converted to a suitable acyl halide, acyl azide or mixed anhydride.

A base may be required at any step in the synthetic scheme of an aryl carboxylic acid conjugate of hydrocodone. Suitable bases include but are not limited to: 4-methylmorpholine (NMM), 4-(dimethylamino)pyridine (DMAP), N,N-diisopropylethylamine, lithium bis(trimethylsilyl)amide, lithium diisopropylamide (LDA), any alkali metal tert.-butoxide (e.g., potassium tert.-butoxide), any alkali metal hydride (e.g., sodium hydride), any alkali metal alkoxide (e.g., sodium methoxide), triethylamine or any other tertiary amine.

Suitable solvents that can be used for any reaction in the synthetic scheme of an aryl carboxylic acid conjugate of hydrocodone include but are not limited to: acetone, acetonitrile, butanol, chloroform, dichloromethane, dimethylformamide (DMF), dimethylsulfoxide (DMSO), dioxane, ethanol, ethyl acetate, diethyl ether, heptane, hexane, methanol, methyl tert.-butyl ether (MTBE), isopropanol, isopropyl acetate, diisopropyl ether, tetrahydrofuran, toluene, xylene or water.

In some embodiments, the prodrug is hydrophobic and thus poorly water soluble. This results in a gel-like consistency or clumpy suspension when the compound is mixed with water. Examples of these prodrugs include, but are not limited to, Piperonylate-HC, 3-OH-4-MeO-Bz-HC, 3-OH-Bz-HC and Gallate-HC. These prodrugs cannot be dosed intranasally in rats due to their lack of water solubility. Not to be bound by any theory, it is assumed that these compounds would also congeal or become clumpy when a human subject tries to inhale them intranasally (“snorting”). This property would not only make an attempt of intranasal abuse an unpleasant experience but would likely also prevent the prodrug from permeating the nose mucosa. As a consequence, these compounds become ineffective for this route of administration.

The present technology provides pharmaceutical kits for the treatment or prevention of drug withdrawal symptoms or pain in a patient. The patient may be a human or animal patient. Suitable human patients include pediatric patients, geriatric (elderly) patients, and normative patients. The kit comprises a specific amount of the individual doses in a package containing a pharmaceutically effective amount of at least one conjugate of hydrocodone of the present technology. The kit can further include instructions for use of the kit. The specified amount of individual doses may contain from about 1 to about 100 individual dosages, alternatively from about 1 to about 60 individual dosages, alternatively from about 10 to about 30 individual dosages, including, about 1, about 2, about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 70, about 80, about 100, and include any additional increments thereof, for example, 1, 2, 5, 10 and multiplied factors thereof, (e.g., ×1, ×2, ×2.5, ×5, ×10, ×100, etc). In one embodiment, the kit contains 18 individual dosages of the combination formulation comprising 6.12 benzhydrocodone and 325 mg acetaminophen in tablet form in a blister pack. In alternative embodiments, the kit may contain about 6, about 12, about 24, about 30, or about 36 individual dosages of the combination formulation in tablet form in a blister pack. In some embodiments, the individual dosages of the combination formulation comprising 6.12 benzhydrocodone and 325 mg acetaminophen are in tablet form contained within a bottle. The bottle may contain about 25, about 50, about 75, about 100, about 125, about 150, about 175, or babout 200 tablets.

The presently described technology and its advantages will be better understood by reference to the following examples. These examples are provided to describe specific embodiments of the present technology. By providing these specific examples, it is not intended limit the scope and spirit of the present technology. It will be understood by those skilled in the art that the full scope of the presently described technology encompasses the subject matter defined by the claims appending this specification, and any alterations, modifications, or equivalents of those claims.

EXAMPLES Example 1 Chemical Stability of Benzoate and Heteroaryl Carboxylate Conjugates of Hydrocodone

Exemplary conjugates of hydrocodone of the present technology and control test conjugates not of the present technology were tested for chemical stability under conditions similar to what a potential drug abuser may use to “extract” the active portion of the molecule, for example dissolved in water, hydrochloric acid or sodium bicarbonate either at ambient temperature or 100° C. The conjugates were placed in a solution of water at either ambient temperature (about 20° C.) or in an oil bath at 100° C. for one hour and the amount of the conjugate that was hydrolyzed under these conditions was measured. Table 1 demonstrates the results, showing that the conjugates did not release hydrocodone at ambient temperature or when heated in water to 100° C. for one hour.

TABLE 1 water Compound ambient 100° C. 4-OH-Bz-HC 0% 0% 2-Abz-HC 0% 0% 4-MeO-Bz-HC 0% 0%

Further, samples of conjugates of hydrocodone of the present technology were tested and compared with samples of other conjugates not of the present technology of hydrocodone (Adipate-HC) for their hydrolysis to hydrocodone after dilution in 1 N hydrochloric acid (HCl) for 1 hour at ambient temperature (˜20° C.) or in an oil bath at 100° C. The percentages indicate how much of the initial amount of conjugate was hydrolyzed under these conditions. The results are shown in Table 2.

TABLE 2 %-release in 1 N HCl Compound ambient 100° C. 4-OH-Bz-HC 0% 30% 2-Abz-HC 0% 16% 3-OH-4-MeO-Bz-HC 0% 35% 2-OH-Bz-HC 3% 27% Adipate-HC 13%  100% 

Samples of each conjugate were dissolved in a solution of 5% NaHCO₃ for one hour at either ambient temperature (˜20° C.) or in an oil bath at 100° C. The percentages indicate how much of the initial amount of conjugate was hydrolyzed under these conditions as shown in Table 3 for the conjugates of the present technology and comparison conjugates not of the present technology (Tyr-Tyr-Phe-Phe-Ile-Hydrocodone (YYFFI-HC) or Adipate-HC).

TABLE 3 %-release in 5% NaHCO₃ Compound ambient 100° C. 4-OH-Bz-HC 1% 23% 3-OH-4-MeO-Bz-HC 0% 36% YYFFI-HC 0% 70% Adipate-HC 3% 100% 

Example 2 Oral PK Profiles of Conjugated Hydrocodone of the Present Technology

Oral PK curves were determined for benzoate-hydrocodone (Bz-HC), a prodrug of the present technology, as compared to two conjugates not within the scope of the present technology: YYFFI-HC and Diglycolate-HC. Rats were orally administered an amount of the conjugate equivalent to 2 mg/kg of freebase hydrocodone and the plasma concentrations of released hydrocodone and of the active metabolite hydromorphone were measured over time by LC-MS/MS. As shown in FIG. 5, the oral PK curves for released hydrocodone were somewhat similar for Bz-HC and YYFFI-HC, but hydrocodone plasma concentrations produced by Bz-HC were mostly significantly higher than hydrocodone concentrations generated by Diglycolate-HC (AUC and C_(max) for Bz-HC were approximately 40% and 50% higher, respectively). Additionally, Bz-HC created higher plasma concentrations of the more potent active metabolite hydromorphone (FIG. 6) than both, YYFFI-HC (AUC and C_(max) for hydromorphone released from Bz-HC were approximately 60% and 80% higher, respectively) and Diglycolate-HC (AUC and C_(max) for hydromorphone released from Bz-HC were approximately 55% and 180% higher, respectively). This suggests that all three compounds undergo a different metabolic pathway and that Bz-HC would have pain relieving effects potentially greater than either example.

Example 3 Intranasal PK Profile of Conjugates of Hydrocodone

Conjugates of hydrocodone of the present technology were tested for abuse resistance capabilities by examining the efficiency of a hydrolysis when administered via routes other than oral. Rats were intranasally treated with conjugate in an amount equivalent to 2 mg/kg of hydrocodone freebase and the concentration of released hydrocodone and of the active metabolite hydromorphone in the plasma of the rat were measured over time by LC-MS/MS. Hydrocodone plasma concentrations were significantly lower for Bz-HC (AUC and C_(max) for hydromorphone released from Adipate-HC were approximately 280% and 60% higher, respectively) as shown in FIG. 7. Moreover, Bz-HC produced very low plasma concentration of hydromorphone when compared to Adipate-HC (AUC and C_(max) for hydromorphone released from Adipate-HC were approximately 750% and 660% higher, respectively) as shown in FIG. 8.

Prodrugs of the present technology provide hydrocodone and hydromorphone plasma concentrations that are significantly lower than respective plasma concentration for unbound Hydrocodone.BT or for other prodrug classes when administered intranasally.

Example 4 Exemplary Intravenous PK Profiles of Conjugates of the Present Technology

The conjugates of hydrocodone of the present technology are hydrophobic, for example, Bz-HC, Nicotinate-HC, 4-MeO-Bz-HC, Piperonylate-HC, 4-OH-Bz-HC, Salicylate-HC, 3-OH-4-MeO-Bz-HC, 3-OH-Bz-HC and Gallate-HC. Therefore, these compounds cannot be administered intravenously at oral equivalent doses because they do not dissolve in a practical amount of water since injectable compounds must be completely in solution, because any solid particle may cause an embolism. The amount of water necessary to dissolve a desirable amount of conjugate would make an injection unfeasible and thus the present compositions and prodrugs have anti-abuse potential as opposed to other hydrocodone conjugates that are water soluble, such as Adipate-HC and Diglycolate-HC which can be administered intravenously at oral equivalent doses.

Example 5 Comparison of Oral PK Profiles of Conjugates of Hydrocodone

The plasma concentrations of hydrocodone released from Bz-HC and Nicotinate-HC were compared to plasma concentrations of hydrocodone generated by unconjugated Hydrocodone.BT after oral administration to rats. Rats were treated with conjugate or unconjugated drug in an amount equivalent to 2 mg/kg of hydrocodone freebase and the plasma concentration of hydrocodone or hydromorphone was measured by LC-MS/MS as demonstrated in FIGS. 9 and 10 respectively. The oral plasma concentration of hydrocodone released from Bz-HC increased similarly to the hydrocodone plasma concentrations observed with Hydrocodone.BT, until it reached C_(max) (C_(max) was approximately equal for both compounds). After T_(max), the hydrocodone plasma concentration for Bz-HC decreased in a slower and more controlled fashion than for unconjugated Hydrocodone.BT (FIG. 9 and FIG. 10). Bz-HC had a higher AUC (AUC was approximately 25% higher, FIG. 9) when compared to Hydrocodone.BT and similar results were observed for the plasma concentrations of the active metabolite hydromorphone (FIG. 10).

Nicotinate-HC, produced hydrocodone and hydromorphone plasma concentrations that were below the respective concentrations found for unconjugated Hydrocodone.BT. The corresponding AUC values, however, were within the range of bioequivalence for the same dose (based on hydrocodone freebase).

2-ABz-HC demonstrated a different release profile after oral administration to rats than Bz-HC or the unconjugated drug Hydrocodone.BT. Rats were treated with an amount equivalent to 2 mg/kg of hydrocodone freebase and the plasma concentration of hydrocodone or hydromorphone was measured by LC-MS/MS over time as shown in FIG. 11 or FIG. 12 respectively. 2-ABz-HC released hydrocodone very slowly indicated by a gradual increase of plasma concentration followed by an attenuated decrease (FIG. 11). This resulted in a flattened PK curve when compared with Hydrocodone.BT (T_(max) for 2-ABz-HC was approximately four times longer, AUC and C_(max) were approximately 35% and 60% lower, respectively). Overall, the PK curve of hydromorphone was also flatter for 2-ABz-HC than for Hydrocodone.BT (FIG. 12) but did show a small initial spike (AUC and C_(max) for 2-ABz-HC were approximately 25% and 50% lower, respectively).

Example 6 Determination of Variation in Plasma Concentrations of Benzoate-Hydrocodone

To determine the variability of the plasma concentration of hydrocodone (HC) and hydromorphone (HM), the coefficient of variation (CV) was calculated for individual animals that were dosed with an amount equivalent to 2 mg/kg of hydrocodone freebase of benzoate-hydrocodone or the unconjugated hydrocodone bitartrate (BT) and the plasma concentrations of hydrocodone and hydromorphone were measured by LC-MS/MS over time. The CV was calculated by dividing the standard deviation of plasma concentrations in individual animals by the mean plasma concentrations of all dosed animals for a given time point. The “average CV” is the mean CV for all time points, as shown in Table 4.

TABLE 4 Average CV Compound HC HM Bz-HC 46 41 Hydrocodone•BT 75 64

The lower average CV for Bz-HC indicates that this prodrug has lower relative variability in plasma concentrations of hydrocodone and hydromorphone across all dosed animals and time points than the unconjugated drug, hydrocodone bitartrate.

Example 7 Synthesis of Conjugates of Hydrocodone

Synthesis of Benzoate-Hydrocodone Freebase

To a solution of hydrocodone freebase (0.596 g, 1.99 mmol) in tetrahydrofuran (25 mL) was added 1 M LiN(SiMe₃)₂ in tetrahydrofuran (5.98 mL). The resulting orange suspension was stirred at ambient temperatures for 30 min. after which benzoate-succinic ester (1.25 g, 5.98 mmol) was added. The resulting mixture was stirred overnight at ambient temperatures and was quenched after 18 h by the addition of 100 mL saturated ammonium chloride solution which was allowed to stir for another 2 h. Ethyl acetate (100 mL) was added to the mixture and washed with saturated ammonium chloride solution (3×100 mL) and water (1×100 mL). Organic extracts were dried over anhydrous MgSO₄, solvent was removed and residue was taken up in 2-isopropanol (50 mL). Water was added until a solid formed. The resulting mixture was chilled, filtered and dried to obtain benzoate-hydrocodone freebase (0.333 g, 0.826 mmol, 42% yield) as a dark brown solid. This synthesis is depicted in FIG. 13A.

Synthesis of 2-Boc-aminobenzoic succinate:

2-Boc-aminobenzoic acid (2.56 g, 10.8 mmol) and N-hydroxysuccinimide (1.37 g, 11.88 mmol) were dissolved in 25 mL of THF. DCC (2.45 g, 11.88 mmol) was added in one portion. The reaction was stirred overnight. The solid was filtered off and rinsed with acetone (2×10 mL). The filtrate was concentrated to dryness and dissolved in 100 mL of acetone. The resulting precipitate (DCU) was filtered off and the filtrate was concentrated to give a solid, which was collected and rinsed with methanol (3×4 mL) to yield 3.26 g (90%) of white product.

Synthesis of 2-Boc-aminobenzoic acid ester of hydrocodone:

To hydrocodone freebase (0.449 g, 1.5 mmol) dissolved in 20 mL of anhydrous THF was added a solution of LiHMDS in THF (1 M, 4.5 mL, 4.5 mmol) over 20 min. The mixture was stirred for 30 min. and 2-Boc-aminobenzoic succinate (1.50 g, 4.5 mmol) was added in one portion. The reaction was stirred for 4 hr and subsequently quenched with 100 mL of sat. NH₄Cl. The mixture was stirred for 1 hr. and extracted with 200 mL of ethyl acetate. The ethyl acetate layer was washed with sat. NaHCO₃ (2×80 mL) and 5% brine (80 mL), dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by silica gel column chromatography (7% MeOH/CH₂Cl₂) to give 449 mg (58%) of an amorphous solid.

Synthesis of 2-aminobenzoic acid ester of hydrocodone dihydrochloride salt:

2-Boc-aminobenzoic acid ester of hydrocodone (259 mg, 0.5 mmol) was stirred in 4 mL of 4 N HCl/dioxane for 4 hr. The solvent was evaporated to dryness and to the residue was added 5 mL of ethyl acetate. The solid was collected and rinsed with ethyl acetate to give 207 mg (84%) of product.

Synthesis of 2-MOM-salicylic succinate:

2-MOM-salicylic acid (3.2 g, 17.6 mmol) and N-hydroxysuccinimide (2.23 g, 19.36 mmol) were dissolved in 40 mL of THF. DCC (3.99 g, 19.36 mmol) was added in one portion. The reaction was stirred overnight. The solid was filtered off and rinsed with acetone (2×10 mL). The filtrate was concentrated and the residue was recrystallized from 10 mL of methanol to give 2.60 g (53%) of a white solid.

Synthesis of 2-MOM-salicylic acid ester of hydrocodone:

To hydrocodone freebase (0.449 g, 1.5 mmol) dissolved in 20 mL of anhydrous THF was added a solution of LiHMDS in THF (1 M, 4.5 mL, 4.5 mmol) over 20 min. The mixture was stirred for 30 min. and 2-MOM-salicylic succinate (1.26 g, 4.5 mmol) was added in one portion. The reaction was stirred for 4 hr. and subsequently quenched with 100 mL of sat. NH₄Cl. The mixture was stirred for 1 hr. and extracted with 200 mL of ethyl acetate. The ethyl acetate layer was washed with sat. NaHCO₃ (2×80 mL) and 5% brine (80 mL), dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by silica gel column chromatography (8% MeOH/CH₂Cl₂) to give 381 mg (58%) of a syrup.

Synthesis of Salicylic acid ester of hydrocodone hydrochloride salt:

To 2-MOM-salicylic acid ester of hydrocodone (380 mg, 0.82 mmol) in 12 mL of methanol was added 0.5 mL of conc. HCl (12 N). The reaction was stirred for 6 hr. The solution was concentrated and residual water was removed by coevaporating with methanol (5×5 mL). The resulting residue was dissolved in 1 mL of methanol followed by 20 mL of ethyl acetate. The cloudy mixture was evaporated to about 4 mL. The resulting solid was collected and rinsed with ethyl acetate to yield 152 mg (41%) of product.

Example 8 Oral PK Profiles of Conjugated Hydrocodone, Hydrocodone, and Hydromorphone in Rats

After oral administration of benzoate-hydrocodone (Bz-HC) to rats, PK curves were determined for intact Bz-HC, hydrocodone, and the active metabolite hydromorphone. Rats were orally administered an amount of the conjugate equivalent to 2 mg/kg of freebase hydrocodone and the plasma concentrations of intact Bz-HC, released hydrocodone, and the active metabolite, hydromorphone, were measured over time by LC-MS/MS. As shown in FIG. 14, the exposure to intact Bz-HC prodrug was much lower than the exposure to hydrocodone or hydromorphone (the AUC for intact Bz-HC was approximately 10% and 3% of the AUC values for hydrocodone and hydromorphone, respectively).

Example 9 Oral PK Profiles of Conjugated Hydrocodone, Hydrocodone, and Hydromorphone in Dogs

After oral administration of benzoate-hydrocodone (Bz-HC) or Hydrocodone.BT to dogs, PK curves were determined for intact Bz-HC (Bz-HC arm only), hydrocodone, and the active metabolite hydromorphone. Dogs were orally administered an amount of Hydrocodone.BT or the conjugate equivalent to 2 mg/kg of freebase hydrocodone. The plasma concentrations of intact Bz-HC, released hydrocodone, and the active metabolite, hydromorphone, were measured over time by LC-MS/MS.

A comparison of plasma concentrations of hydrocodone released from Bz-HC and Hydrocodone.BT is shown in FIG. 15. Overall, the plasma concentrations of hydrocodone generated by both compounds were quite similar. The systemic exposure to hydrocodone was somewhat reduced for Bz-HC when compared to Hydrocodone.BT (the AUC value of hydrocodone for Bz-HC was approximately 72% of the AUC value for Hydrocodone.BT). The C_(max) value of hydrocodone for Bz-HC was approximately 92% of the C_(max) value for Hydrocodone.BT.

A comparison of the plasma concentrations of the active metabolite, hydromorphone, following oral administration of Bz-HC or Hydrocodone.BT is shown in FIG. 16. Systemic exposure and maximum plasma concentrations of hydromorphone were similar for both compounds. The AUC and C_(max) values of hydromorphone for Bz-HC were approximately 103% and 109% of the respective values for Hydrocodone.BT

A comparison the plasma concentrations of intact Bz-HC and hydrocodone released from Bz-HC is shown in FIG. 17. Similar to the results seen in rats, the plasma concentrations of intact Bz-HC prodrug in dogs were low when compared to the plasma concentrations of hydrocodone (the AUC value for intact Bz-HC was approximately 10% of the AUC value for hydrocodone).

Example 10 Intravenous PK Profiles of Conjugated Hydrocodone, Hydrocodone, and Hydromorphone in Rats

Bz-HC (0.30 mg/kg) was administered intravenously to rats. Due to its poor water solubility (or solubility in PBS), 0.30 mg/kg was close to the maximum dose that could be administered intravenously to rats. PK curves were determined for intact Bz-HC, hydrocodone, and the active metabolite hydromorphone. The plasma concentrations of intact Bz-HC, released hydrocodone, and the active metabolite, hydromorphone, were measured over time by LC-MS/MS. The resulting PK curves are shown in FIG. 18.

Example 11 Oral PK Profiles of Hydrocodone and Hydromorphone Following Various Dosages of Bz-HC in Rats

Bz-HC was orally administered to rats at dosages of 0.25, 0.50, 1.00, 2.00, 3.00, or 4.00 mg/kg. The plasma concentrations of hydrocodone or hydromorphone were measured by LC-MS/MS, as demonstrated in FIGS. 19 and 20, respectively. The exposures (AUC) to hydrocodone and hydromorphone at doses of Bz-HC between 0.25 and 4.00 mg/kg were fairly linear. The respective C_(max) values, however, were more variable, particularly for hydromorphone. The maximum plasma concentrations of hydromorphone did not significantly change at doses above 2.00 mg/kg of Bz-HC.

Description of Bioanalytical Methods Used in Examples 12-13

Validated LC/MS/MS methods were used to measure plasma concentrations of BzHC-, hydrocodone, hydromorphone and acetaminophen (APAP). The lower limits of quantitation (LLOQ) for Bz-HC, hydrocodone, hydromorphone, and APAP in plasma were 25 pg/mL, 250 pg/mL, 25 pg/mL, and 0.025 μg/mL, respectively.

Description of Pharmacokinetic and Statistical Analysis Conducted in Examples 12-13

Actual blood sampling collection times were used in all PK analyses. Per protocol times were used to calculate mean plasma concentrations for graphical displays. Pharmacokinetic parameters for hydrocodone, hydromorphone, and APAP were calculated using standard equations for non-compartmental analysis. Only plasma concentrations that were greater than the LLOQs for the respective assays were used in the pharmacokinetic analysis.

Example 12 Bz-HC.HCl/APAP Human Pharmacokinetic Studies

A study was conducted to assess the pharmacokinetics of Bz-HC, hydrocodone and hydromorphone after administration of single oral doses of Bz-HC.HCl/acetaminophen (APAP) tablets (6.67 mg/325 mg) and hydrocodone bitartrate (HB)/APAP (7.5 mg/325 mg) at three different dose levels (4, 8, and 12 tablets) under fasted conditions.

This was a single-center, randomized, double-blind, active- and placebo-controlled, and 7-period crossover. After completing an overnight fast (minimum 8 hours), subjects received each of the following 7 treatments according to their randomized treatment sequence:

A. 12 placebo capsules

B. 12 Bz HC.HCl/APAP 6.67 mg/325 mg tablets (over encapsulated) (80.04 mg Bz HC.HCl/3,900 mg acetaminophen)

C. 4 placebo capsules+8 Bz HC.HCl/APAP 6.67 mg/325 mg tablets (over encapsulated) (53.36 mg HC.HCl/APAP/2,600 mg acetaminophen)

D. 8 placebo capsules+4 Bz HC.HCl/APAP 6.67 mg/325 mg tablets (over encapsulated) (26.68 mg HC.HCl/APAP/1,300 mg acetaminophen)

E. 12 HB/APAP 7.5 mg/325 mg tablets (over encapsulated) (90 mg HB/3,900 mg acetaminophen)

F. 4 placebo capsules+8 HB/APAP 7.5 mg/325 mg tablets (over encapsulated) (60 mg HB/2,600 mg acetaminophen)

G. 8 placebo capsules+4 HB/APAP 7.5 mg/325 mg tablets (over encapsulated) (30 mg HB/1,300 mg acetaminophen)

On dosing days blood samples were collected for Bz-HC.HCl, hydrocodone, and hydromorphone analysis at the following sampling times: within 1 hour predose and at 0.5, 1, 1.5, 1.75, 2, 3, 4, 6, 8, 10, 12, and 24 hour postdose. As shown in FIGS. 21a and 21b , at the low-dose (4 tablets, for example) and mid-dose (8 tablets, for example), the composition of Bz-HC.HCl/APAP 6.67 mg/325 mg provided a therapeutically bioequivalent AUC or C_(max) or both for hydrocodone at about lower than 53 mg when compared to an equivalent molar amount of unconjugated hydrocodone. At the high-dose (12 tablets, for example), the composition of Bz-HC.HCl/APAP 6.67 mg/325 mg exhibited an improved AUC and rate of release of hydrocodone over time when compared to unconjugated hydrocodone over the same time period. The composition at the high-dose exhibited lower exposure to hydrocodone at about more than 53 mg when compared to an equivalent molar amount of unconjugated hydrocodone. The composition at the high-dose also exhibited a lower peak exposure (C_(max)) to hydrocodone at about more than 53 mg when compared to an equivalent molar amount of unconjugated hydrocodone.

As shown in FIGS. 22a and 22b , at the low-dose (4 tablets, for example) and mid-dose (8 tablets, for example), the composition of Bz-HC.HCl/APAP 6.67 mg/325 mg provided a therapeutically bioequivalent AUC or C_(max) or both for hydromorphone at about lower than 53 mg when compared to an equivalent molar amount of unconjugated hydromorphone. At the high-dose (12 tablets, for example), the composition of Bz-HC.HCl/APAP 6.67 mg/325 mg exhibited an improved AUC and rate of release of hydromorphone over time when compared to unconjugated hydrocodone over the same time period. The composition at the high-dose also exhibited a lower exposure to hydromorphone at about more than 53 mg when compared to an equivalent molar amount of unconjugated hydrocodone. The composition at the high-dose also exhibited lower peak exposure (C_(max)) to hydromorphone at about more than 53 mg when compared to an equivalent molar amount of unconjugated hydrocodone.

A summary of the comparative PK data for Bz-HC.HCl/APAP and HB/APAP is presented in the following Table 5.

Hydrocodone^(a) Hydromorphone^(a) PK Parameter 4 Tablets 8 Tablets 12 Tablets 4 Tablets 8 Tablets 12 Tablets C_(max) 96.4% 90.2% 90.8% 88.8% 91.2% 87.5% AUC_(last) 98.4% 94.2% 95.8% 92.8% 94.9% 98.8% AUC_(INF) 98.2% 94.8% 97.1% 107.0%  99.2% 107.6%  AUC_(0-0.5) 96.9% 88.7% 86.1% 88.5% 92.0% 86.4% AUC₀₋₁ 96.7% 89.6% 86.9% 88.7% 92.0% 86.9% AUC₀₋₂ 95.5% 90.7% 89.4% 89.1% 91.4% 89.7% AUC₀₋₄ 94.7% 91.5% 91.9% 89.9% 92.4% 93.3% AUC₀₋₈ 95.6% 92.2% 93.3% 90.0% 92.4% 95.0% AUC₀₋₂₄ 98.4% 94.2% 95.8% 92.8% 94.9% 98.8% ^(a)Entries represent the percent-ratio of the respective mean PK parameter for Bz-HC•HCl/APAP to the same mean PK parameter for HB/APAP. Percentages <100% indicate a lower value of the respective PK parameter for Bz-HC•HCl/APAP compared to HB/APAP.

Mean peak exposure to hydrocodone was lower with Bz HC.HCl/APAP at the mid- and high-dose but similar at the low-dose when compared to HB/APAP (Table 5). The ratio of mean C_(max) values for Bz-HC.HCl/APAP:HB/APAP in terms of hydrocodone exposure was greater than 96% at the low-dose, such as 4 tablets. The ratio of mean C_(max) values for Bz-HC.HCl/APAP:HB/APAP in terms of hydrocodone exposure was about 90-91% at the mid- and high-dose, such as 8 and 12 tablets.

Drug users seek fast onset of euphoria for fast reward which plays an important role in reinforcing behavior and addiction. As a result, lower opioid exposure, particularly in the first 1-2 hours following administration, is less desirable by drug users and more desirable for abuse-deterrent opioid therapies. At the mid- and high-dose, the partial areas under the curve for hydrocodone from 0 to 0.5 hours post-dose (AUC_(0-0.5)), from 0 to 1 hour post-dose (AUC₀₋₁), and from 0 to 2 hours post-dose (AUC₀₋₂) showed the most significant reduction in exposure with Bz-HC.HCl APAP compared to HB/APAP (Table 5).

Example 13 Effects on Hydrocodone-Induced Respiratory Depression and Hypoxia in Recreational Drug Users

The characteristic pattern of opioid-induced respiratory depression is a reduced respiratory rate (bradypnea) with deep, sighing ventilations. Patients may often be conscious but lack the drive to breathe. Once given verbal commands to breathe, the patient may comply and take breaths when instructed to do so. Carbon dioxide (CO₂) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. The loss of central respiratory drive is typical of opioids, but this feature is difficult to quantify. If respiration is the maintenance of adequate arterial CO₂ and O₂ tensions, then respiratory depression can be defined as the failure to maintain those arterial CO₂ and O₂ tensions.

Therefore, a primary threshold of respiratory depression may the development of hypoxemia, the physical condition of having the presence of an abnormally low level of oxygen in the circulating blood. Hypoxemia can subsequently result in hypoxia, the physical condition of insufficient oxygen supply to the body or regions of the body. During clinically significant respiratory depression, reduced oxygen saturation usually occurs in combination with a reduction in ventilatory performance, often manifesting as any combination of a reduction in respiratory rate, reduction in end-tidal volume, reduction in minute volume, reduction in arterial pH, reduction in O₂.

During the study described above (Example 12) incidence of hypoxia was recorded for each treatment (Table 6). One out of sixty-four subjects and one out of sixty-five subjects experienced hypoxia at the low-dose (4 tablets) with Bz-HC.HCl/APAP and HB/APAP, respectively. At the mid-dose (8 tablets), three out of sixty-five subjects receiving Bz-HC.HCl/APAP experienced hypoxia compared to nine out sixty-five patients with HB/APAP. Thirteen out of sixty-five subjects receiving Bz-HC.HCl/APAP experienced hypoxia at the high-dose (12 tablets) compared to twenty-one out sixty-seven subjects with HB/APAP. Therefore, there was a lower incidence of hypoxia in subjects treated with Bz-HC.HCl/APAP compared to HB/APAP at the mid- and high-dose. In another words, Bz-HC.HCl/APAP has reduced a side effect of respiratory depression resulting in lower than normal concentration of oxygen in arterial blood of the patient and hypoxia in the patient compared to unconjugated hydrocodone. This reduction was more pronounced at higher doses (more than 4 tablets, for example) at which hypoxia occurs more often and presents a higher safety risk. A summary of the incidence of hypoxia by treatment is presented in the following Table 6.

4 Tablets 8 Tablets 12 Tablets Bz-HC•HCl/ HB/ Bz-HC•HCl/ HB/ Bz-HC•HCl/ HB/ APAP APAP APAP APAP APAP APAP Total N 64 65 65 65 65 67 Hypoxia (N)  1  1  3  9 13 21 (%) (1.6%) (1.5%) (4.6%) (13.8%) (20.0%) (31.3%)

Example 14 Bz-HC HCl/APAP Human Bioavailability Studies—Single Dose

Comparative bioavailability studies were conducted to assess (1) the bioavailability of hydrocodone following oral administration of a single dose of 6.67 mg/325 mg Bz-HC HCl/APAP compared to a single dose of hydrocodone bitartrate/ibuprofen (7.5 mg/200 mg) to healthy subjects under fasted conditions, and (2) the bioavailability of acetaminophen following oral administration of a single dose of 6.67 mg/325 mg Bz-HC HCl/APAP compared to a single dose of tramadol hydrochloride/acetaminophen (37.5 mg/325 mg) to healthy subjects under fasted conditions. 28 subjects completed the study comparing Bz-HC HCl/APAP to hydrocodone bitartrate/ibuprofen, and 27 subjects completed the study comparing Bz-HC HCl/APAP to tramadol hydrochloride/acetaminophen. A summary of the pharmacokinetic parameters from each study is provided below in Tables 7 and 8, respectively.

TABLE 7 Bz-HC HCl/APAP HB/Ibuprofen Parameter* (6.67/325) (7.25/200) Hydrocodone C_(max) (pg/mL) 21,061 ± 4,426 (28) 20,943 ± 3,792 (28) T_(max) (h) 1.00 (28) 1.13 (28) [0.50-2.00] [1.00-3.00] AUC(0-t) (hxpg/mL) 132,618 ± 34,198 (28) 131,552 ± 26,333 (28) AUC(inf) (hxpg/mL) 136,499 ± 34,899 (28) 135,320 ± 27,211 (28) t½ (h)  4.19 ± 0.64 (28)  4.22 ± 0.64 (28) *Arethmetic mean ± standard deviation (N) except T_(max) for which the median (N) [Range] is reported.

TABLE 8 Bz-HC HCl/APAP Tramadol-HCl/APAP Parameter* (6.67/325) (37.5/325) Acetaminophen C_(max) (μg/mL) 3.81 ± 1.30 (27) 3.74 ± 1.08 (27) T_(max) (h) 1.00 (27) 1.25 (27) [0.50-4.00] [0.50-4.00] AUC(0-t) (hxpg/mL) 15.1 ± 4.48 (27) 15.9 ± 5.61 (27) AUC(inf) (hxpg/mL) 15.5 ± 4.57 (25) 15.7 ± 4.47 (25) t½ (h) 5.27 ± 1.86 (25) 4.50 ± 1.08 (25) *Arithmetic mean ± standard deviation (N) except T_(max) for which the median (N) [Range] is reported.

The data show that the composition of 6.67 mg/325 mg Bz-HC HCl/APAP provided bioequivalent AUC and C_(max) for hydrocodone compared to the immediaterelease-tablet of 7.5 mg hydrocodone/200 mg ibuprofen, and provided bioequivalent AUC and C_(max) for acetaminophen compared to the immediaterelease-tablet of 37.5 mg tramadol/325 mg acetaminophen.

Example 15 Bioavailability Study Under Fasted Conditions

A comparative study was conducted to assess the bioavailability of hydrocodone, hydromorphone, and acetaminophen after administration of single oral doses of Bz-HC HCl/acetaminophen (APAP) tablets (6.67 mg/325 mg) and hydrocodone bitartrate (HB)/APAP (7.5 mg/325 mg). This was an open-label, single-dose, randomized, two-treatment, two-period, two-sequence, crossover bioavailability study in which subjects received two separate single dose administrations under fasted conditions. Twenty-four healthy subjects completed the study. A summary of the PK parameters is provided below in Table 9

TABLE 9 Bz-HC HCl/APAP HB-/APAP Parameter* (6.67/325) (7.5/325) Hydrocodone C_(max) (pg/mL) 16,859 ± 4,153 (23)  19,383 ± 4,893 (23)  T_(max) (h) 1.25 (23) 1.25 (23) [0.50-3.00] [0.50-2.00] AUC(0-t) 112,088 ± 28,774 (23)  119,005 ± 31,368 (23)  (hxpg/mL) AUC(inf) 115,773 ± 29,099 (23)  122,914 ± 31,321 (23)  (hxpg/mL) t½ (h) 4.21 ± 0.57 (23) 4.14 ± 0.61 (23) Acetaminophen C_(max) (μg/mL) 4.07 ± 1.23 (23) 4.43 ± 1.41 (23) T_(max) (h) 0.50 (23) 0.50 (23) [0.50-2.00] [0.50-2.00] AUC(0-t) 16.4 ± 3.99 (23) 16.1 ± 3.68 (23) (hxpg/mL) AUC(inf) 17.2 ± 3.70 (22) 17.3 ± 3.06 (21) (hxpg/mL) t½ (h) 4.93 ± 0.98 (22) 5.11 ± 1.19 (21) *Arithmetic mean ± standard deviation (N) except T_(max) for which the median (N) [Range] is reported.

The data show that the composition of Bz-HC HCl/APAP provided bioequivalent C_(max) and AUC for hydrocodone, and provided bioequivalent AUC for acetaminophen with comparable acetaminophen C_(max). FIG. 23 illustrates that the composition of Bz-HC.HCl/APAP 6.67 mg/325 mg provided a bioequivalent AUC and C_(max) for hydrocodone and the active metabolite hydromorphone when compared with hydrocodone bitartrate (HB)/APAP (7.5 mg/325 mg).

Example 16 Bioavailability Study Under Fasted and Fed Conditions

A study was conducted to assess the effect of food on the bioavailability and pharmacokinetics of Bz-HC HCl/APAP in 38 healthy subjects, compared to fasted condition. Coadministration—of Bz-HC HCl/APAP with a high-fat, high-calorie meal showed a slight decrease in the rate but no change in the extent of hydrocodone absorption; and no difference in rate and extent of acetaminophen absorption. The effect of a high-fat, high-calorie meal on pharmacokinetics is similar between Bz-HC HCl/APAP and an immediate release tablet of 7.5 mg hydrocodone/325 mg acetaminophen. The PK parameters for hydrocodone and acetaminophen after oral administration of Bz-HC HCl/APAP tablet, 6.67 mg/325 mg under fasted and fed conditions are shown in Table 10 below.

TABLE 10 PK parameters of hydrocodone and acetaminophen after oral administration of Bz-HC HCl/APAP tablet, 6.67 mg/325 mg under fasted and fed conditions. Parameter^(a) Fed Fasted Hydrocodone C_(max) (ng/mL) 16.04 ± 3.60 (40)  19.18 ± 4.84 (38)  T_(max) (h) 2.50 (40) 1.25 (38) [0.50-4.00] [0.50-3.00] AUC_(inf) (h ng/mL) 130.91 ± 29.45 (40)  125.73 ± 36.78 (38)  t_(1/2) (h) 4.53 ± 0.70 (40) 4.33 ± 0.67 (38) Acetaminophen C_(max) (μg/mL) 3.34 ± 1.01 (39) 4.05 ± 1.30 (38) T_(max) (h) 1.50 (39) 1.00 (38) [0.50-4.00] [0.50-3.00] AUC_(inf) (h μg/mL) 15.0 ± 3.53 (36) 14.7 ± 3.87 (36) t_(1/2) (h) 5.64 ± 1.58 (36) 4.78 ± 1.30 (36) ^(a)Arithmetic mean ± standard deviation (N) except T_(max) for which the median (N) [Range] is reported. The data show that Bz-HC HCl/APAP can be administered without regard to food.

Example 17 Bz-HC HCl/APAP Human Multi-Dose Pharmacokinetic Study

A study was conducted to assess the pharmacokinetics of Bz-HC, hydrocodone, and hydromorphone after oral administration of multiple doses in 24 healthy subjects. Subjects were administered 2 tablets of Bz-HC HCl/APAP, 6.67 mg/325 mg orally every 4 hours for a total of 13 doses. Steady state for hydrocodone and acetaminophen was achieved after 24 hours and between 24 and 36 hours, respectively. The accumulation ratios for hydrocodone C_(max) and AUC values were 1.85-fold and 2.03-fold, respectively. The accumulation ratios for acetaminophen C_(max) and AUC values were 1.38-fold and 1.80-fold, respectively. No measurable exposure to Bz-HC was shown even after the maximum dose of 2 tablets every 4 hours for 13 doses. A summary of the PK data is shown in Table 11.

TABLE 11 Parameter* Day 1 Day 4 Hydrocodone C_(max) (pg/mL) 33,946 ± 8,407 (24)  62,788 ± 14,751 (24) T_(max) (h) 1.00 (24) 1.25 (24) [0.50-4.00] [0.50-2.00] AUC(0-4) 92,940 ± 20,158 (24) 195,074 ± 47,655 (24)  (hxpg/mL) AUC(0-t) 212,948 ± 52,803 (24)  432,752 ± 118,669 (24) (hxpg/mL) AUC(inf) 219,357 ± 57,283 (24)  —† (hxpg/mL) t½ (h) 4.45 ± 0.59 (24) 4.87 ± 0.63 (24) Acetaminophen C_(max) (μg/mL) 7.95 ± 2.16 (24) 11.0 ± 2.34 (24) T_(max) (h) 0.50 (24) 1.00 (24) [0.50-3.00] [0.50-1.50] AUC(0-4) 17.6 ± 4.25 (24) 29.8 ± 6.19 (24) (hxpg/mL) AUC(0-t) 30.5 ± 12.7 (24) 55.0 ± 13.6 (24) (hxpg/mL) AUC(inf) 28.9 ± 7.07 (23) —† (hxpg/mL) t½ (h) 4.79 ± 1.21 (23) 6.84 ± 2.42 (23) *Arithmetic mean ± standard deviation (N) except t_(max) for which the median (N) [Range] is reported.

Example 18 Bz-HC.HCl/APAP Human Intranasal Pharmacokinetics Study

A randomized, double-blind, double-dummy, active- and placebo-controlled, 5-period crossover study was conducted to assess the abuse potential of crushed Bz-HC.HCl/APAP and HB/APAP tablets administered intranasally in non-dependent, recreational opioid users. The study consisted of a Screening Visit, a Qualification Phase, a Treatment Phase, and a Follow-up Visit. The Qualification Phase consisted of a Naloxone Challenge Test to confirm that subjects were not physically dependent on opioids and a Drug Discrimination Test to ensure that subjects were able to differentiate between the psychoactive effects of a single intranasal dose of 2 crushed tablets of 7.5 mg/325 mg HB/APAP versus placebo.

Each treatment included an intranasal dose and an intact (oral) dose of study drug in a double-blind, double-dummy manner. The placebo for intranasal administration consisted of microcrystalline cellulose powder and the placebo for oral administration consisted of over-encapsulated lactose tablets. The treatments administered are presented in Table 12 below. Amounts of hydrocodone in Bz-HC.HCl/APAP and HB/APAP are equimolar.

TABLE 12 Treat- ment Crushed Intranasal Dose Oral Intact Dose (Capsules) A Placebo Placebo (975 mg microcrystalline 2 over-encapsulated lactose cellulose powder) tablets B Placebo Bz-HC•HCl (975 mg microcrystalline 2 over-encapsulated tablets cellulose powder) 6.67/325 mg (13.34/650 mg) C Bz-HC•HCl/APAP Placebo 2 crushed tablets 6.67/325 2 over-encapsulated lactose mg (13.34/650 mg) tablets D HB/APAP Placebo 2 crushed tablets 7.5/325 2 over-encapsulated lactose mg (15/650 mg) tablets E Placebo HB/APAP tablets over- (975 mg microcrystalline encapsulated 2 over- cellulose powder) encapculated tablets 7.5/325 mg (15/650 mg) APAP = acetaminophen; HB = hydrocodone bitartrate The amount of placebo powder (975 mg) administered intranasally is the approximate average of 2 tablets of Bz-HC•HCl/APAP and HB/APAP.

Forty-six subjects were randomized to treatment and 42 subjects were included in the analyses. Study validity was confirmed by statistically significant (P<0.0001) differentiation of the positive control, HB/APAP, relative to placebo for the primary endpoint Drug Liking E_(max). Differentiation was statistically significant for HB/APAP relative to placebo via both the oral and IN routes of administration.

Following intranasal administration of Bz-HC.HCl/APAP (13.34/650 mg), early systemic hydrocodone exposures were reduced by approximately 50% (AUC_(0-0.5)[P=0.0044]), 29% (AUC₀₋₁[P=0.0005]), and 15% (AUC₀₋₂[P=0.0003]) relative to intranasal administration of HB/APAP. C_(max) of hydrocodone was reduced by approximately 11% for Bz-HC.HCl/APAP vs HB/APAP, but this difference was within conventional bioequivalence criteria (90% Cl within 80-125%). AUC₀₋₈, AUC₀₋₂₄, AUC_(last) and AUC_(inf) were similar for both treatments (P=0.1212 or more). The median (range) T_(max) values were similar between Bz-HC.HCl/APAP (1.23 hours [0.52-2.23]) and HB/APAP (1.22 hours [0.25-2.23]).

For the comparison of IN Bz-HC.HCl/APAP vs. IN HB/APAP, Drug Liking at early time intervals (AUE_(0-0.5), AUE₀₋₁, AUE₀₋₂) was statistically significantly lower for IN Bz-HC.HCl/APAP (P≤0.0079) (Table 13). There were small numerical but no statistical differences in Drug Liking E_(max) and other abuse-related endpoints that rely on maximal effect (E_(max)) including High, and Take Drug Again (Table 14).

TABLE 13 LS Mean and Differences in LS mean of AUE values (up to 2 hours postdose) of IN Bz-HC•HCl/APAP versus IN HB/APAP IN Bz-HC•HCl/APAP IN Bz- versus IN HB/APAP HC•HCl/APAP IN HB/APAP Difference in Parameter LS Mean (SE) LS Mean (SE) LS Mean P-Value AUE_(0-0.5) 30.2 (0.9) 36.2 (0.9) −6.0 <0.0001 AUE₀₋₁ 63.6 (2.0) 72.7 (2.0) −9.2 <0.0001 AUE₀₋₂ 129.9 (4.1)  141.8 (4.1)  −11.9 0.0079

TABLE 14 Summary Statistics of Maximum Scores (E_(max)) on Drug Liking, High and Take Drug Again, Following Intranasal Administration of Bz-HC•HCl/APAP, HB/APAP, and Placebo. VAS Scale (100 point) intranasal Bz-HC•HCl/APAP HB/APAP (n = 42) Crushed Crushed Placebo Drug Liking* Mean (SE) 75.9 (2.3) 79.0 (2.7) 53.0 (1.2)  Median    74.0 (50-100)    80.0 (50-100) 51.0 (50-85) (Range) High** Mean (SE) 61.8 (4.6) 59.1 (5.1) 8.8 (3.8)  Median  68.5 (0-100)  67.5 (0-100)  0.0 (0-100) (Range) Take Drug Again* Mean (SE) 69.5 (3.9) 74.5 (3.9) 48.2 (2.2)  Median  68.0 (0-100)  81.5 (0-100) 50.0 (0-100) (Range) *Bipolar scale (0 = maximum negative response, 50 = neutral response, 100 = maximum positive response) **Unipolar scale (0 = maximum negative response, 100 = maximum positive response)

Example 19 Extraction and Hydrolysis Study

Bz-HC.HCl/APAP tablets (intact or crushed) were evaluated for the possibility and potential for individuals to extract Bz-HC from the formulation and then convert extracted Bz-HC to hydrocodone. HB/APAP tablets (intact or crushed) were evaluated under the same conditions for the potential to extract hydrocodone. Extraction solvents included a number of organic solvents ranging from very non-polar to very polar, and aqueous solvents with pH ranging from 1 to 13.

Overall, the efficiency of extracting Bz-HC from Bz-HC.HCl/APAP was similar compared to the efficiency of extracting hydrocodone from HB/APAP.

The covalent bond between benzoic acid and hydrocodone has to be broken to release hydrocodone from Bz-HC.HCl. The data show that hydrolysis of Bz-HC.HCl to hydrocodone with acids and bases is a difficult process.

In the present specification, use of the singular includes the plural except where specifically indicated.

The presently described technology is now described in such full, clear, concise and exact terms as to enable any person skilled in the art to which it pertains, to practice the same. It is to be understood that the foregoing describes preferred embodiments of the technology and that modifications may be made therein without departing from the spirit or scope of the invention as set forth in the appended claims. 

The invention claimed is:
 1. A method of treating a patient having acute pain, comprising orally administering to the patient a pharmaceutically effective amount of a composition comprising benzhydrocodone and acetaminophen in an amount of 6.12 mg benzhydrocodone and 325 mg acetaminophen.
 2. The method of claim 1, wherein the composition is in the form of a tablet.
 3. The method of claim 2, wherein the tablet is an immediate release tablet.
 4. The method of claim 3, wherein the tablet is administered as a dosage of 1 to 2 tablets every 4 to 6 hours.
 5. The method of claim 4, wherein the dosage is up to 12 tablets in a 24 hour period.
 6. The method of claim 4, wherein the dosage is up to 10 tablets in a 24 hour period.
 7. The method of claim 4, wherein the dosage is up to 8 tablets in a 24 hour period.
 8. The method of claim 4, wherein the dosage is up to 6 tablets in a 24 hour period.
 9. The method of claim 4, wherein the dosage is up to 4 tablets in a 24 hour period.
 10. The method of claim 4, wherein administration of the composition is for a period of time not exceeding 14 days.
 11. The method of claim 3, wherein the tablet is contained in a blister pack.
 12. The method of claim 3, wherein the benzhydrocodone is in the form of benzhydrocodone hydrochloride, and wherein the 6.12 mg benzhydrocodone is equivalent to 6.67 mg benzhydrocodone hydrochloride.
 13. The method of claim 3, wherein the 6.12 mg benzhydrocodone is equivalent to 4.54 mg hydrocodone.
 14. A method of treating a patient having pain, comprising orally administering to the patient from 1 to 2 immediate release tablets every 4 to 6 hours, wherein each tablet comprises a composition comprising 6.12 mg benzhydrocodone and 325 mg acetaminophen.
 15. The method of claim 14, wherein up to 12 tablets are administered in a 24 hour period.
 16. The method of claim 14, wherein up to 10 tablets are administered in a 24 hour period.
 17. The method of claim 14, wherein up to 8 tablets are administered in a 24 hour period.
 18. The method of claim 14, wherein up to 6 tablets are administered in a 24 hour period.
 19. The method of claim 14, wherein up to 4 tablets are administered in a 24 hour period.
 20. The method of claim 14, wherein administration of the composition is for a period of time not exceeding 14 days.
 21. A method of treating a patient having pain, comprising orally administering to the patient from 1 to 2 immediate release tablets every 4 to 6 hours, wherein each tablet comprises the composition of claim
 1. 22. The method of claim 21, wherein up to 12 tablets are administered in a 24 hour period.
 23. The method of claim 21, wherein up to 10 tablets are administered in a 24 hour period.
 24. The method of claim 21, wherein up to 8 tablets are administered in a 24 hour period.
 25. The method of claim 21, wherein up to 6 tablets are administered in a 24 hour period.
 26. The method of claim 21, wherein up to 4 tablets are administered in a 24 hour period.
 27. The method of claim 21, wherein administration of the composition is for a period of time not exceeding 14 days.
 28. The method of claim 21, wherein the pain is acute pain.
 29. A method of treating a patient having pain, comprising orally administering to the patient a pharmaceutically effective amount of a composition that comprises from about 3 mg to about 54 mg benzhydrocodone hydrochloride and optionally from about 150 mg to about 350 mg acetaminophen.
 30. The method of claim 29, wherein the composition comprises about 3.33 mg, about 4.45 mg, about 8.90 mg, about 13.34 mg, about 26.68 mg, or about 53.36 mg benzydrocodone hydrochloride.
 31. The method of claim 30, wherein the composition comprises about 150 mg, about 162 mg, about 216.67 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg or about 350 mg acetaminophen.
 32. The method of claim 29, wherein the composition comprises about 4.45 mg benzydrocodone hydrochloride, and about 325 mg acetaminophen.
 33. The method of claim 32, wherein the composition is in the form of a tablet.
 34. The method of claim 33, wherein the tablet is an immediate release tablet.
 35. The method of claim 34, wherein the tablet is administered as a dosage of 1 to 2 tablets every 3 to 4 hours.
 36. The method of claim 35, wherein the dosage is up to 12 tablets in a 24 hour period.
 37. The method of claim 29, wherein the composition comprises 8.9 mg benzydrocodone hydrochloride, and 325 mg acetaminophen.
 38. The method of claim 37, wherein the composition is in the form of a tablet.
 39. The method of claim 38, wherein the tablet is administered as a dosage of 1 to 2 or 1 to 1.5 tablets or 1 tablet every 4 to 6 hours.
 40. The method of claim 39, wherein the dosage is up to 12 tablets in a 24 hour period.
 41. The method of claim 29, wherein the composition comprises 13.34 mg benzydrocodone hydrochloride.
 42. The method of claim 41, wherein the 13.34 mg benzhydrocodone hydrochloride is equivalent to 12.24 mg benzhydrocodone.
 43. The method of claim 29, wherein the composition comprises 13.34 mg benzydrocodone hydrochloride, and 325 mg acetaminophen.
 44. The method of claim 43, wherein the composition is in the form of a tablet.
 45. The method of claim 44, wherein the tablet is administered as a dosage of 1 to 2 or 1 to 1.5 tablets or 1 tablet every 4 to 6 hours.
 46. The method of claim 45, wherein the dosage is up to 6 tablets in a 24 hour period. 